Research Models

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180 Models

Name Other Names Strain Name Genetic Background Gene Mutation Modification Info Modification Disease Neuropathology Behavior/Cognition Other Phenotype Availability Primary Paper Visualization
Mouse Models (174)
3xTg-AD, The LaFerla mouse B6;129-Psen1<tm1Mpm> Tg(APPSwe,tauP301L)1Lfa/Mmjax (129X1/SvJ x 129S1/Sv)F1-Kitl<+> APP, PSEN1, MAPT APP KM670/671NL (Swedish), MAPT P301L, PSEN1 M146V Single-cell embryos from mice with knock-in of PSEN1 with the PS1M146V mutation were injected with two human transgenes (APP with the Swedish mutation and MAPT with the P30IL mutation). Transgenes integrated at a single locus under the control of the mouse Thy1.2 promoter. APP: Transgenic; PSEN1: Transgenic; MAPT: Transgenic Alzheimer's Disease Age-related, progressive neuropathology including plaques and tangles. Extracellular Aβ deposits by 6 months in frontal cortex, more extensive by 12 months. No tau pathology at 6 months, but evident at 12 months. Synaptic dysfunction, including LTP deficits, prior to plaques and tangles. Cognitive impairment by 4 months. Impairments first manifest as a retention/retrieval deficit and not as a learning deficit, and occur prior to plaques and tangles. Deficits in both spatial and contextual based paradigms. Clearance of intraneuronal Aβ by immunotherapy rescues the early cognitive deficits in a hippocampal-dependent task. The Jackson Lab; available through the JAX MMRRC Stock# 034830; Live Oddo et al., 2003 Yes
5XFAD APP/PS1, Tg6799, Tg-5xFAD B6SJL-Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax (C57BL/6 x SJL)F1 APP, PSEN1 APP KM670/671NL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V Two transgenes: mutant human APP with the APP Swedish, Florida and London mutations and containing the 5' untranslated region driven by the mouse Thy1 promoter and 2) mutant human PSEN1 including the M146L and L286V mutations driven by the mouse Thy1 promoter. APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Amyloid pathology starting at 2 months, including amyloid plaques. Accumulation of intraneuronal Aβ before amyloid deposition. Gliosis and synapse degeneration. Neuron loss in cortical layer 5 and subiculum. No neurofibrillary tangles. Age-dependent memory deficits including spatial memory, stress-related memory, and memory stablization. Motor phenotype and reduced anxiety. The Jackson Lab; available through the JAX MMRRC Stock# 034840; Live Oakley et al., 2006 Yes
C57BL/6J APP APP KM670/671NL (Swedish), APP T714I (Austrian) Transgene-expressing mutant APP with the Swedish mutation (K670N/M671L) and the Austrian mutation (T714I) under the control of the Thy1.2 promoter. APP: Transgenic Alzheimer's Disease Progressive amyloid deposition in the cerebral cortex by approximately 9-12 months. Unknown. Optogenetic stimulation induced epileptic seizures. Unknown Yamada et al., 2009 No
Dan-amyloid, BRI2-Danish, ADan precursor protein C57BL/6J ITM2B (BRI2) BRI2: Familial Danish Dementia (FDD) duplication Transgenic mice with human BRI2 gene containing the Familial Danish Dementia (FDD) mutation under the control of the Syrian hamster prion protein promoter. The FDD mutation is a 10-nucleotide duplication in the region of the stop codon in the BRI2 gene, resulting in a C-terminally elongated protein. ITM2B (BRI2): Transgenic Familial Danish Dementia, Alzheimer's Disease, Cerebral Amyloid Angiopathy ADan deposition starts in the hippocampus and meningeal vessels at 2 months and increases with age. By 18 months, deposition is widespread. The majority of amyloid deposits are associated with the vasculature, where they destroy the integrity of the vessel wall and lead to microhemorrhages. Parenchymal amyloid plaques surrounded by microglia and dystrophic neurites are also present. Impaired performance in Morris water maze, due to a combination of both motor deficits (i.e. reduced swim speed) and spatial learning deficits reported at 18-20 months. Open field test at 18-20 months also showed an anxiety-related phenotype. Adult mice fail to gain weight with age. Alopecia. Kyphosis. Available through Mathias Jucker Coomaraswamy et al., 2010 Yes
Amyloid β (A4) precursor-like protein 2 knock-out, APLP2 KO B6.129S7-Aplp2tm1Dbo/J 129S7,C57BL/6J; backcrossed to C57BL/6J Aplp2 Inactivation of the mouse APLP2 gene by deleting a 1.1kb region containing the promoter and exon 1 using a targeting vector containing a PGK-neomycin expression cassette for positive selection and a MC1-TK cassette for negative selection. Aplp2: Knock-Out Alzheimer's Disease Not observed. Not observed. Homozygous animals are viable, normal in size, fertile, and do not display any gross physical or behavioral abnormalities up to 22 months of age. No impairments in axonal outgrowth of olfactory neurons following bulbectomy. The Jackson Lab: Stock# 004142; Cryopreserved von Koch et al., 1997 No
APOE2 KI C57BL/6; 129P2, backcrossed to C57BL/6J APOE The human APOE2 cDNA sequence was knocked-in at the endogenous mouse APOE locus; inserted in frame with non-coding sequences, exon 1, intron 1 and the first 18 bp of exon 2 such that expression is regulated by endogenous regulatory elements and the mouse APOE gene inactivated. APOE: Knock-In Alzheimer's Disease, Traumatic Brain Injury Unknown. Unknown. 2-fold higher level of steady state APOE in brain and higher APOE in serum compared with APOE3 and APOE4 KI animals. Highest levels of serum cholesterol and triglycerides after a 6hr fast. No longer available through Bruce Lamb Mann et al., 2004 No
APOE2 Humanized Knock-in B6.129P2-Apoetm1(APOE*2)Mae N9 C57BL/6 APOE Targeted gene replacement of the endogenous murine APOE gene with the human APOE2 allele. Targeting construct included exons 2-4 of APOE2. APOE: Knock-In Alzheimer's Disease Unknown. Unknown. Characteristics of type III hyperlipoproteinemia. Plasma cholesterol and triglyceride levels 2-3x higher than APOE3 mice. Impaired clearance of very-low-density lipoprotein (VLDL) particles. Atherosclerotic plaques. Taconic: Stock# 1547-F and 1547-M Sullivan et al., 1998 No
APOE3 KI C57BL/6; 129P2, backcrossed to C57BL/6J APOE The human APOE3 cDNA sequence was knocked-in at the endogenous mouse APOE locus; inserted in frame with non-coding sequences, exon 1, intron 1 and the first 18bp of exon 2 such that expression is regulated by endogenous regulatory elements and the mouse APOE gene inactivated. APOE: Knock-In Alzheimer's Disease, Traumatic Brain Injury Unknown. Unknown. Intermediate brain APOE and serum cholesterol levels compared with mice with knock-in of APOE4 or APOE2. No longer available through Bruce Lamb Mann et al., 2004 No
APOE3 Humanized Knock-in B6.129P2-Apoetm2(APOE*3)Mae N8 129 x C57BL/6; back-crossed to C57/BL6 APOE Targeted replacement of the endogenous mouse APOE gene with the human APOE3 allele. Targeting vector contained exons 2-4 of human APOE3. APOE: Knock-In Alzheimer's Disease Unknown. Unknown. On a standard diet, homozygous mice have normal cholesterol and triglyceride levels, but are more susceptible than wild-type animals to diet-induced atherosclerosis. Taconic: Stock# 1548-F and 1548-M Sullivan et al., 1997 No
APOE4 KI C57BL/6; 129P2, backcrossed to C57BL/6J APOE The human APOE4 cDNA sequence was knocked-in at the endogenous mouse APOE locus; inserted in frame with non-coding sequences, exon 1, intron 1 and the first 18 bp of exon 2 such that expression is regulated by endogenous regulatory elements and the mouse APOE gene inactivated. APOE: Knock-In Alzheimer's Disease, Traumatic Brain Injury Unknown. Unknown. Human ApoE is detectable in serum and astrocytes. Compared to mice with knock-in of APOE2 or APOE3, APOE4 mice had the lowest serum cholesterol after a 6 hour fast. No longer available through Bruce Lamb Mann et al., 2004 No
APOE4 Humanized Knock-in B6.129P2-Apoetm3(APOE*4)Mae N8 129 x C57BL/6, back-crossed to C57BL/6 APOE Targeted replacement of the endogenous murine APOE gene with the human APOE4 allele; targeting construct contained exons 2–4 of APOE4. APOE: Knock-In Alzheimer's Disease Unknown. Unknown. Increased risk of atherosclerosis. Elevated cholesterol, APOE, and APOB-48 on a high fat diet. Taconic: Stock# 1549-F or 1549-M Knouff et al., 1999 No
APOE KO, APOE -/-, APOE TM1 B6.129P2-Apoetm1Unc N11 129 x C57BL/6 APOE Inactivation of the endogenous mouse APOE by homologous recombination and insertion of a neomycin cassette. APOE: Knock-Out Alzheimer's Disease Unknown. Unknown. Viable; healthy. Undetectable ApoE protein in plasma. Plasma cholesterol 5x higher than wild-type. Artherosclerotic lesions which progress to occlusions of coronary artery by 8 months. Taconic: Stock# APOE-M and APOE-F Piedrahita et al., 1992 No
B6-Tg/Thy1APP23Sdz B6(Cg)-Tg(Thy1-APP)3Somm/J C57BL/6 APP APP KM670/671NL (Swedish) Transgene containing human APP (isoform 751) containing the Swedish (KM670/671NL) mutation under the murine Thy1 promoter. APP: Transgenic Alzheimer's Disease, Cerebral Amyloid Angiopathy Aβ deposits first observed at 6 months. Congophilic plaques increase in size and number with age and are surrounded by activated microglia, astrocytes, and dystrophic neurites containing hyperphosphorylated tau (although no neurofibrillary tangles). Neuronal loss in the CA1 region of the hippocampus. Mice also develop CAA, and microhemorrages occur at later ages. Spatial memory defects in Morris Water maze at 3 months and progresses with age. Memory deficits in passive avoidance were observed in 25 month-old mice, but not at younger ages. Hyperactivity observed between the ages of 6 weeks to 6 months. It is not known whether this persists or resolves in older animals. Abnormalities in open field test and impaired performance on rotorod observed from 3 months. Available through The Jackson Laboratory Stock# 030504, Live. Sturchler-Pierrat et al., 1997 Yes
C57BL/6J APP, PSEN1 PSEN1 R278I This is a cross between APP23 mice, which overexpress APP751 with the Swedish mutation driven by the murine Thy1 promoter, and PSEN1 knock-in mice expressing human PSEN1 with the R278I mutation under the endogenous promoter. APP: Transgenic; PSEN1: Knock-In Alzheimer's Disease Amyloid deposition by 6 months of age in the cortex and hippocampus. Abundant reactive astrocytes in the vicinity of plaques. Elevated Aβ43 in the brain by 3 months. High density of cored plaques. Pyroglutamate Aβ (N3pE-Aβ) associated with amyloid plaques. Short-term memory deficits apparent by 3-4 months as measured by the Y maze. Reduced γ-secretase activity. Available through Takaomi Saido Saito et al., 2011 Yes
APP(SL)PS1KI, APPxPS1-Ki, APPSL/PS1KI, APP(SL)/PS1(KI), APP/PS1KI The PS1KI line was established in 129SV and backcrossed >7 times to C57BL/6 background. The PS1KI were bred with APPSL mice on a C57BL background (two rounds) to obtain a homozygote PS1KI and heterozygote APP. APP, PSEN1 APP KM670/671NL (Swedish), APP V717I (London), PSEN1 M233T, PSEN1 L235P This animal is a cross between a PSEN1 knock-in line and an APP over-expressing line. The PS1 knock-in line was generated by introducing two point mutations in the wild-type mouse PSEN1, corresponding to the mutations M233T and L235P. APP751SL overexpresses human APP751 carrying the London (V717I) and Swedish (K670N/M671L) mutations under the control of the Thy1 promoter. APP: Transgenic; PSEN1: Knock-In Alzheimer's Disease Acceleration of extracellular Aβ deposition compared to the single transgenics. Age-dependent neuronal loss in the hippocampus with extensive neuronal loss in the CA1/2 at 10 months with detection as early as 6 months in female mice. Intraneuronal Aβ and thioflavin-S-positive deposits before neuronal loss. Astrogliosis in proximity of Aβ-positive neurons. Age-dependent impairments in working memory as measured by the Y maze and T-maze continuous alternation task. No deficit at 2 months, but deficits at 6 and 12 months compared to PS1KI littermates. Viable and fertile. 6 month-old animals develop decreases in body weight, and a spinal deformity (kyphosis) is common. Impaired neurogenesis. Available through Thomas Bayer or Benoit Delatour Casas et al., 2004 Yes
tg13592 C57BL/6 x DBA/2 APP Transgene consisting of the signal plus 99-amino acid carboxyl-terminal sequence (SbC) of APP under the control of a cytomegalovirus enhancer/β-actin promoter. APP: Transgenic Alzheimer's Disease No neuropathology up to age 29 months; however, pathology reminiscent of inclusion body myopathy observed at 6-12 months: Aβ-immunoreactive deposits in skeletal muscle fibers. Muscle fibers with Aβ-immunoreactive deposits increased with age and also became vacuolated. Hypoactivity. The acquisition of place learning in the Morris water maze task was impaired. Higher cytochrome oxidase activity in thalamic nuclei. High levels of Aβ peptides in the plasma. Available through Ken-ichiro Fukuchi, University of Illinois College of Medicine at Peoria Fukuchi et al., 1996 No
APP-Dutch, Tg-APP(Dutch), APP E693Q, APP Dutch C57BL/6J-Tg(Thy1-APPDutch) C57BL/6J APP APP E693Q (Dutch) Transgenic mice with human APP751 bearing the E693Q mutation under the murine Thy1 promoter. APP: Transgenic Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch type, Cerebral Amyloid Angiopathy, Alzheimer's Disease Increased Aβ40/42 ratio. Extensive vascular Aβ deposition starting at 22-24 months appearing first in leptomeningeal vessels followed by cortical vessels, leading to smooth muscle cell degeneration, hemorrhages, and neuroinflammation. Parenchymal amyloid plaques are not observed.  Unknown. Available through Mathias Jucker Herzig et al., 2004 Yes
Osaka, APP(OSK)-Tg, APP Osaka mutation transgenic, APPOSK-Tg mice, APPOSK mice B6C3F1, back-crossed to C57Bl/6 APP APP E693del (Osaka) Transgenic expression of human APP695 with the Osaka mutation driven by the mouse prion promoter. APP: Transgenic Alzheimer's Disease Age-dependent accumulation of Aβ oligomers within hippocampal and cortical neurons, but negligible deposits of extracellular amyloid. Abnormal tau phosphorylation, but no overt tangle pathology. Synaptic loss and gliosis in hippocampus and cerebral cortex. Late neuronal loss in the CA3 region of the hippocampus. Memory impairment by eight months as measured by the Morris water maze. Specifically, reduced spatial reference memory in the Morris water maze compared to mice expressing comparable levels of wild-type human APP. Available through Hiroshi Mori and Takami Tomiyama Tomiyama et al., 2010 Yes
APP KI, line ADF Strain of origin: (129X1/SvJ x 129S1/Sv)F1-Kitl<+>; C57BL/6 and maintained on a mixed background APP APP KM670/671NL (Swedish), APP V717I (London), APP E693Q (Dutch) Knock-in of wild-type mouse APP exon 16 (truncated after residue KM), FLAG tag (2 repeats), a stop codon, a poly A signal region from the human growth hormone gene and an additional copy of exon 16 carrying the Swedish mutation and a modified exon 17 with the London and Dutch mutations. APP: Knock-In Alzheimer's Disease Unknown. Unknown. The Jackson Lab: Stock# 008390; Cryopreserved No
APP null, APP KO B6.129S7-Apptm1Dbo/J C57BL/6J APP Inactivation of the mouse APP gene by replacing a 3.8 kb sequence encoding the promoter and exon 1 with a neomycin resistance cassette. APP: Knock-Out Alzheimer's Disease Elevated reactive gliosis by 14 weeks in the hippocampus and parts of the neocortex. Impaired spatial learning as measured by the water maze at 4 and 10 months. Hypoactivity and decreased locomotor activity and forelimb grip strength. Homozygous knock-out mice weigh 15-20% less than age-matched wild-type mice. The Jackson Lab: Stock# 004133; Live Zheng et al., 1995 No
APP NL-F/NL-F C57BL/6 APP APP KM670/671NL (Swedish), APP I716F (Iberian) Knock-in of APP sequence including introns 15 to 17. Sequence was modified to contain a humanized Aβ region and the Swedish and Beyreuther/Iberian mutations. APP: Knock-In Alzheimer's Disease Elevated Aβ peptides accumulating into plaques starting at 6 months. Microgliosis and astrocytosis, especially around plaques. Reduced synaptophysin and PSD-95 indicative of synaptic loss. No tangle pathology or neurodegeneration. Memory impairment by 18 months as measured by the Y maze. No significant impairment in the Morris water maze. No overexpression of APP. Generates wild-type levels of AICD. Available through Takaomi Saido Saito et al., 2014 Yes
APP NL-G-F/NL-G-F C57BL/6 APP APP KM670/671NL (Swedish), APP I716F (Iberian), APP E693G (Arctic) Knock-in of APP sequence including introns 15 to 17. Sequence was modified to contain a humanized Aβ region and three pathogenic mutations (Swedish, Beyreuther/Iberian, and Arctic). APP: Knock-In Alzheimer's Disease Aggressive amyloidosis with deposition in the cortex beginning at 2 months and approaching saturation by 7 months. Aβ deposition in heterozygous mice at 4 months. Subcortical amyloidosis. Exacerbated microgliosis and astrocytosis compared to APPNL-F mice. Reduced synaptophysin and PSD-95 indicative of synaptic loss. No tangle pathology or neurodegeneration. Memory impairment by 6 months as measured by the Y maze. No overexpression of APP. Wild-type levels of AICD. Available through Takaomi Saido Saito et al., 2014 Yes
APPPS1-21 B6-Tg(Thy1-APPswe; Thy1-PS1 L166P) C57BL/6J APP, PSEN1 APP KM670/671NL (Swedish), PSEN1 L166P Human transgenes APP KM670/671NL and PSEN1 L166P, both under the control of the Thy1 promoter. Integration site is on lower arm of chromosome 2 between 40 and 60 cm. APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Amyloid plaque deposition starts at approximately 6 weeks in the neocortex. Amyloid deposits in the hippocampus appear at 3-4 months, and in the striatum, thalamus and brainstem at 4-5 months. Phosphorylated tau-positive neuritic processes have been observed in the vicinity of all congophilic amyloid deposits, but no fibrillar tau inclusions are seen.   Cognitive deficits in spatial learning and memory in the Morris water maze reported at 7 months. Impaired reversal learning of a food-rewarded four-arm spatial maze task at 8 months. Aβ42 concentration in CSF decreases with age, with a 50% reduction by 6 months and an 80% reduction by 18 months. Aβ40 concentration also decreases, but less robustly (45% by 18 months). CSF concentration of total tau increases, starting at 6 months, and reaches a 5-fold increase by 18 months. Available through Mathias Jucker Radde et al., 2006 Yes
APPswe/PSEN1dE9/MAPT, APPswe/PSEN1dE9/CaMKIIa-tTa/TRE-rTg21221 B6.C3 x B6.129 x FVB APP, PSEN1, MAPT APP KM670/671NL (Swedish), PSEN1: deltaE9 APPswe/PSEN1dE9 mice were crossed with B6.129-Tg(CK-tTa) mice where the CaMKIIa promotor drives expression of tetracycline transactivator (tTA) in forebrain neurons. Offsping were then crossed to the rTg21221 line with a responder transgene of wildtype human tau. APP: Transgenic; PSEN1: Transgenic; MAPT: Knock-In Alzheimer's Disease Tau accumulations, dystrophic neurites, astrocytosis, neuronal loss, and synapse loss were more pronounced adjacent to cortical plaques. Tangles were not observed. No data. N/A APPswe/PSEN1dE9 mice available through The Jackson Lab Stock# 004462. Jackson et al., 2016 Yes
Tg2576;Pdgfrβ+/- APPsw mice on C57BL/6; Pdgfrβ+/- mice on 129S1/SvlmJ. APP, PDGFRB APP KM670/671NL (Swedish) Progeny of APPsw transgenics (Tg2576) crossed with pericyte-deficient mice. Tg2576 express human APP with the Swedish double mutation driven by the hamster prion promoter. Pericyte-deficient mice were made by disrupting the Pdgfrβ gene using a PGKneobpA expression cassette to replace a 1.8 kb genomic segment spanning the signal peptide to the second immunoglobulin domain of PDGFRβ. APP: Transgenic; PDGFRB: Knock-Out Alzheimer's Disease Amyloid plaques; elevated brain interstitial human and murine Aβ due to reduced clearance of soluble Aβ, cerebral amyloid angiopathy, tau hyperphosphorylation and related pathology. Neurite loss and neuronal loss in the cortex and hippocampus. Age-associated cognitive impairment as measured by hippocampal-dependent tasks, including nest building, burrowing, and novel object recognition. Progressive loss of pericytes due to reduced Pdgfrβ signaling. Early and progressive blood brain barrier breakdown, indicated by cerebral accumulation of IgG. Reduced microvascular circulation, indicated by reduced capillary length. Available through Berislav Zlokovic Sagare et al., 2013 Yes
APPSwDI/NOS2 bigenic mice, APPSDI/NOS2KO, CVN B6.Cg-Nos2tm1Lau Tg(Thy1-APPSwDutIowa)BWevn/Mmjax C57BL/6J; C57BL/6N APP, NOS2 APP KM670/671NL (Swedish), APP E693Q (Dutch), APP D694N (Iowa) APPSwDI x NOS2 knockout animals. APPSwDI transgene expresses APP (isoform 770) with Swedish, Dutch, and Iowa mutations under the control of the mouse Thy1 promoter. NOS2 was disrupted by homologous recombination. The calmodulin binding domain of NOS2 was replaced by the neomycin resistance gene and the reading frame disrupted. APP: Transgenic; NOS2: Knock-Out Alzheimer's Disease Plaques especially in the thalamus and subiculum. Aggregated, hyperphosphorylated tau tangles. Neuronal loss especially of NPY neurons in the hippocampus and subiculum. More severe pathology than Tg-SwDI alone. Severe learning and memory deficits. Impaired spatial memory compared to Tg-SwDI as measured by the radial arm maze and the Barnes maze at 52-56 weeks. Decreased neuropeptide Y staining throughout the hippocampus, particularly in the CA3 region and subiculum. The Jackson Lab; available through the JAX MMRRC Stock# 034849; Cryopreserved. Charles River: CVN mouse Colton et al., 2008, Wilcock et al., 2008 Yes
APPSw, hAPPSwe (line 71) , hAPPSwe (line 72), huAPPSw B6.D2-Tg(Thy1-APPSwe)71Blt; B6.D2-Tg(Thy1-APPSwe)72Blt C57BL/6, DBA/2, crossed to C57BL/6 APP APP KM670/671NL (Swedish) Transgene with human APP751 with the Swedish mutation driven by the Thy1.2 promoter. APP: Transgenic Alzheimer's Disease Amyloid plaques by 17-18 months in the neocortex and hippocampus with detection of 5-10 fold more Aβ40 than Aβ42. Plaque burden significantly lower than in the double transgenic PS2APP. Lower levels of insoluble Aβ40 and Aβ42 than the PS2APP mouse at 16-18 months. Unknown. Available through Laurence Ozmen Richards et al., 2003 No
R1.40, APP(K670/M671), R1.40-YAC B6.129-Tg(APPSw)40Btla/Mmjax (129X1/SvJ x 129S1/Sv)F1-Kitl<+> APP APP KM670/671NL (Swedish) A 650 kb YAC transgene containing the entire human APP gene and ~250 kb of flanking sequence was mutated to include the Swedish mutation (K670N/M671L). Founder animals (line R1.40) were backcrossed to C57BL/6J. APP: Transgenic Alzheimer's Disease By 14-16 months, homozygotes have diffuse and compact Aβ deposits in the frontal cortex, by 18-20 months plaques throughout the cortex and olfactory bulb with occasional deposits in the corpus callosum and hippocampus. No tangles, but some changes in phosphorylated tau. Reactive astrocytes and microglia by 14-16 months. Unknown. Increased mortality in young homozygous animals, especially females. At 3-4 months mice maintained on the C57BL/6J background exhibit spontaneous seizure-like activity as measured by EEG and are more susceptible to kainic acid-induced seizures. The Jackson Lab; available through the JAX MMRRC Stock# 034831; Cryopreserved Lamb et al., 1997 Yes
APP(695)Swe C3B6-Tg(APP695)3Dbo/Mmjax C3H/HeJ x C57BL/6J; backcrossed to C57BL/6J APP APP KM670/671NL (Swedish) Transgene is a chimeric mouse/human APP (isoform 695) with a "humanized" Aβ domain and the Swedish mutation under the control of the mouse prion protein promoter. APP: Transgenic Alzheimer's Disease Age-associated increase in Aβ40 and Aβ42 and some amyloid deposition at advanced age. Congenic animals showed normal reference and working memory up to 12-14 months. The Jackson Lab; available through the JAX MMRRC Stock# 034828; Cryopreserved Borchelt et al., 1996, Savonenko et al., 2003 Yes
B6.Cg-Tg(Prnp-App/APPswe)E1-2Dbo/Mmjax C3H/HeJ x C57BL/6J; backcrossed to C57BL/6J APP APP KM670/671NL (Swedish) Transgene is a chimeric mouse/human APP (isoform 695) with a "humanized" Aβ domain carrying the Swedish mutation under the control of the mouse prion protein promoter. APP: Transgenic Alzheimer's Disease Age-dependent increase in Aβ42, with low levels at 6-14 months and high levels at 24-26 months. No cognitive impairment in tasks of reference or working memory at 12-14 months. More than half of the female hemizygous mice do not survive past 15 months of age. The Jackson Lab; available through the JAX MMRRC Stock# 034835; Cryopreserved Savonenko et al., 2003, Borchelt et al., 1996 No
APP YAC Swe/Lon (line J1.96), B6-J1-96 B6.129S4-Tg(APPSwLon)96Btla/Mmjax 129S4/SvJae-derived J1 ES cells; backcrossed to C57BL/6 APP APP KM670/671NL (Swedish), APP V717I (London) A 650 kb YAC transgene containing the entire human APP gene carrying the Swedish and London mutations with ~ 250 kb of flanking sequence; founder animals (line J1.96) have a single copy of the transgene. APP: Transgenic Alzheimer's Disease No amyloid plaques observed at 2 years. Unknown. The Jackson Lab; available through the JAX MMRRC Stock# 034837; Cryopreserved Lamb et al., 1997 No
APPSwe (line C3-3)/PSEN1(A246E)(line N-5), APP/PS1, APPswe + PS1 (A246E), APP + PS1, AP mouse, C3-3/N-5 B6C3-Tg(APP695)3Dbo Tg(PSEN1)5Dbo/J Origin: (C57BL/6J x C3H/HeJ)F2 APP, PSEN1 APP KM670/671NL (Swedish), PSEN1 A246E Double transgenic mice; cross of mice expressing human PSEN1 with the A246E mutation driven by the mouse prion protein promoter with mice expressing chimeric APP (isoform 695) with the Swedish mutation driven by the mouse prion promoter. Chimeric APP was created by replacing the mouse Aβ sequence with the cognate human sequence. APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Amyloid plaques by 9 months, starting in the hippocampus and subiculum. Plaques later develop in the cortex; the striatum and thalamus are relatively spared. Amyloid pathology is more severe in females. Dystrophic neurites and gliosis in the cortex and hippocampus. Poor nest building. Reduced retention in a learned passive avoidance task. Increased immobility time in forced swim task. Age-associated impairment in acquisition and retention in the Morris water maze. No impairment in a position discrimination T-maze task. Increased irritability. The Jackson Lab: Stock# 003378; Cryopreserved Borchelt et al., 1997, Borchelt et al., 1996 Yes
APP/PS1, APPswe/PS1deltaE9, line 85, APP(swe) + PSEN1DeltaE9, APdE9, Borchelt mice B6C3-Tg(APPswe,PSEN1dE9)85Dbo/Mmjax C57BL/6 x C3H)F2 APP, PSEN1 APP KM670/671NL (Swedish), PSEN1: deltaE9 Co-injection of a vector for chimeric mouse/human APP carrying the Swedish mutation and a second for mutant PSEN1 (deltaE9) controlled by independent mouse prion protein promoter elements. The two transgenes co-integrated and co-segragate as a single locus. APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Occasional Aβ deposits by 6 months with abundant plaques in the hippocampus and cortex by 9 months and a progressive increase in plaques up to 12 months. No tangles. Decrease in synaptic markers and increase in complement immunoreactivity. Cognitive impairment (e.g., deficits in spatial memory and contextual memory). Changes in spontaneous behavior (e.g., nest-building, burrowing). High incidence of seizures. High incidence of seizures. Tail phenotype that is believed to be due to genetic background. Bladder dysfunction. The Jackson Lab; available through the JAX MMRRC Stock# 034829; Live Jankowsky et al., 2001, Jankowsky et al., 2004 Yes
APPSwe(line C3-3) X PS1dE9 (line S-9), C3-3/PS1-dE9, C3-3 x S-9 B6.Cg-Tg(APP695)3Dbo Tg(PSEN1dE9)S9Dbo/J Line C3-3: C57BL/6J; Line S-9: hybrid strain C3H/HeJ;C57BL/6J) backcrossed to C57BL/6J APP, PSEN1 APP KM670/671NL (Swedish), PSEN1: deltaE9 Double transgenic mice: 1) Line C3-3: mice express a chimeric mouse/human APP gene (isoform 695) carrying the Swedish mutation and 2) Line S-9: mice express a mutant human PSEN1 gene carrying the deletion of exon 9 (dE9) driven by the mouse prion promoter. APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Elevated Aβ42 and plaques in the hippocampus and cortex. No tangles. Reduced cholinergic markers. Age-related cognitive deficits; episodic memory more sensitive than reference memory. No differences at 6 months, but detectable at 18 months. At 19 months, small but significant decrease in acetylcholinesterase activity in the hippocampus and choline acetyl transferase (ChAT) in the hippocampus and cortex. The Jackson Lab; available through the JAX MMRRC Stock# 034833; Cryopreserved Savonenko et al., 2005 Yes
NSE-APPsw Origin: C57BL/6 x DBA/2 APP APP KM670/671NL (Swedish) Transgene containing human APP (isoform 695) bearing the Swedish mutation under the control of neuron specific enolase (NSE) promoter. APP: Transgenic Alzheimer's Disease Increased Aβ42 in the cortex and hippocampus of 12 month old mice, but no plaques. Increased tau phosphorylation and TUNEL-stained nuclei relative to control mice. In water maze tests, 12 month old mice had longer escape latencies than age-matched control mice. Metallothionein expression was increased in brain astrocytes and was thought to attenuate Aβ-induced neurotoxicity.  Increased Cox-2 and caspase-3 compared to age-matched control mice.   Available through Yong K Kim Hwang et al., 2004 No
Knock-in of APP(V642I) Origin:C57BL/6 x CBA; chimeric mice breed to CD-1 mice APP APP V717I (London) Targeted knock-in of the V642I mutation into exon 17 of the mouse APP gene using homologous recombination and the Cre-loxP system. APP: Transgenic Alzheimer's Disease Increased Aβ42(43) relative to Aβ40 at 29 months, but without neuritic plaques, neurofibrillary tangles, massive neuronal loss, or brain atrophy. At 27-29 months mice displayed long-term memory deterioration. Acquisition of spatial memory is slightly affected, but no deterioration in short-term working memory. No difference in open field test or elevated plus maze suggesting no difference in overall behavioral patterns or activity levels. Unknown Kawasumi et al., 2004 Yes
APPlon, APP-london, APPLd, APP-ld, APP(V717I), APP[V717I], APP.V717I, APP(London) (line 2), APP/LD/2 Thy1-hAPP.V717I (C57BL/6.FVB/N) Originally generated on FVB/N background; available at reMYND as C57BL/6xFVB/N APP APP V717I (London) Transgene containing human APP (isoform 695) with the London mutation driven by the Thy1 promoter. APP: Transgenic Alzheimer's Disease, Cerebral Amyloid Angiopathy Plaques start in the subiculum, spreading to the frontal cortex as dense and diffuse aggregates. Prominent amyloid deposits in brain vessels after 15 months. Microbleeds. Amyloid-associated inflammation. CSF Aβ42/Aβ40 ratio decreases from 15 months. Dystrophic neurites containing hyperphosphorylated tau, but no tangle pathology. From the age of 6 months, spatial and non-spatial orientation and memory deficits by Morris water maze. Impaired associative learning. Increased agitation/anxiety from 8 weeks. Reduced ambulation, especially with age. Hyperactivity and aggression. Increased mortality (72% by day 180). Increased incidence of seizures. Available through the KU Leuven Research and Development Office and reMYND Moechars et al., 1999 Yes
APPxPS1, APP(V717I)x PS1(A246E), APP[V717I]x PS1[A246E], APP.V717I x PS1.A246E Thy1-hAPP.V717I ( C57BL/6)x Thy1-hPS1.A246E (FVB/N) Originally generated on FVB/N background; available at reMYND as C57BL/6xFVB/N APP, PSEN1 APP V717I (London), PSEN1 A246E The transgene overexpresses the mutant human amyloid protein precursor APP (isoform 695), which bears the London (V717I) mutation, and human presenilin-1 with the A246E mutation, both under the control of the neuron-specific murine Thy1 promoter. APP: Multi-transgene; PSEN1: Transgenic Alzheimer's Disease, Cerebral Amyloid Angiopathy Soluble, oligomeric Aβ at 2 months and increases with age. Amyloid plaques at 6-9 months, earlier than APP(V717I) single transgenics. Plaques start in the subiculum and spread to the frontal cortex. Amyloid-associated inflammation. CAA pathology at 8 months; microbleeds at 12-15 months. Dystropic neurites containing hyperphosphorylated tau, but no tangle pathology. From the age of 5 months, spatial and non-spatial orientation and memory deficits by Morris Water Maze. Impaired associative learning, hyperactivity, anxiety, and aggression. Available through reMYND Dewachter et al., 2000 Yes
APPSw/Ind/Arc, APPSwedish/Indiana/Arctic, hAPP Arc line Inbred C57BL/6 APP APP KM670/671NL (Swedish), APP V717F (Indiana), APP E693G (Arctic) A human APP minigene with the Swedish, Indiana, and Arctic mutations driven by the platelet-derived growth factor β-chain promoter. APP: Transgenic Alzheimer's Disease, Cerebral Amyloid Angiopathy Parenchymal neuritic plaques by 2 months accompanied by dystrophic neurites. Prominent hippocampal Aβ deposition by 3-4 months. Relatively low Aβ42/Aβ40 ratio. Comparable cerebrovascular amyloid deposition to J20. At 3-4 months the Arc48 mouse was able to learn a task involving escape to a cued platform in the Morris water maze, but had an impaired ability to use extramaze cues to navigate to the hidden platform. Premature lethality. Trend toward hyperactivity. Reduced calbindin and Fos levels in the dentate gyrus. Cryopreserved. Contact Lennart Mucke Cheng et al., 2004 Yes
arcAbeta Origin: B6D2 F1 APP APP KM670/671NL (Swedish), APP E693G (Arctic) Human APP695 transgene containing the Swedish (K670N/M671L) and Arctic mutation (E693G) was generated by site-directed mutagenesis. APP: Transgenic Alzheimer's Disease At 6 months intracellular punctate deposits of Aβ abundant in cortex and hippocampus, but overt β-amyloid plaques not apparent until 9-15 months. Severe CAA also present at this age with dense Aβ aggregates in blood vessels walls and spreading into the parenchyma. Cognitive impairments from the age of 6 months measured in the Morris water maze and Y-maze. Deficits in synaptic plasticity, LTP, and functional connectivity as measured by resting-state fMRI. Unknown Knobloch et al., 2007 Yes
B6;CB-Tg(Thy1-PSEN1*M146V/Thy1-APP*swe)10Arte Co-injection of transgenes into B6CBF1 oocytes, back-crossed to C57BL/6 APP, PSEN1 APP KM670/671NL (Swedish), PSEN1 M146V Co-integration of two transgenes, mutant APP carrying the K670N/M671L mutation, and mutant PSEN1 carrying the M146V mutation, both under the control of the Thy-1 promoter. APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Robust early plaque development (by 3 months in homozygotes, 5 months in hemizygotes), predominantly congophilic dense-core amyloid plaques surrounded by dystrophic neurites and gliosis. Some diffuse plaques and cerebral amyloidosis. No tau tangles. Neurons have reduced dendritic length, surface area, and branches. Age-related learning and memory deficits, especially episodic memory, in select paradigm-specific tasks by 12 months. Good breeding capabilities and no premature death. Unknown Willuweit et al., 2009 Yes
BACE1 -/-, BACE1 KO B6.129-Bace1tm1Pcw/J C57BL/6J BACE1 Homologous recombination was used to disrupt a 2kb section of BACE1 containing exon 1 replacing it with a neomycin selection cassette and the HSV thymidine kinse gene. BACE1: Knock-Out Alzheimer's Disease Hypomyelination in the hippocampus and cerebral cortex, but normal axonal development. Increased thermal pain sensitivity as measured by a hot plate test. Decreased grip strength. Homozygous mice are viable, fertile, normal in size. No BACE1 protein is detected by Western blot. Primary cultures of cortical neurons do not secrete Aβ1-40/42, Aβ11-40/42 or β-C terminal fragments (β-CTFs). The Jackson Lab: Stock# 004714; Live Cai et al., 2001 No
BACE2delta6, BACE2 KO B6;129P2-Bace2tm1Bdes/J Strain of origin: 129P2/OlaHsd BACE2 Cre mediated recombination was used to remove exon 6 of BACE2. A targeting vector containing a loxP site and hygromycin resistance gene flanked by FRT sites was introduced into intron 5 and a second loxP site was inserted within intron 6. Heterozygous mice were crossed with mice expressing Cre under the ubiquitous phosphoglycerate kinase promoter to delete exon 6 in progeny. BACE2: Knock-Out Alzheimer's Disease Not observed. Not observed. BACE2 deficient fibroblasts produced higher levels of Aβ compared with wild-type cells. The Jackson Lab: Stock# 005618; Cryopreserved Dominguez et al., 2005 No
BRI2-Aβ40 B6.Cg-Tg(Prnp-ITM2B/APP695*40)1Emcg/J B6C3, backcrossed to C57BL/6J to generate congenic strain Construct encodes a fusion protein of the BRI protein and Aβ40 driven by the mouse prion promoter; Aβ40 is secreted through proteolytic cleavage of the protein at a furin cleavage site immediately preceding Aβ40. Transgenic Alzheimer's Disease No overt amyloid pathology or detergent-insoluble amyloid-β. Hemizygous mice on a mixed background (C57/B6//C3H) have intact cognition as measured by fear conditioning at 12 and 14-17 months. The Jackson Lab: Stock# 007180; Cryopreserved McGowan et al., 2005 No
BRI2-Aβ42, BRI-Abeta42 B6.Cg-Tg(Prnp-ITM2B/APP695*42)A12Emcg/J B6C3, backcrossed to C57BL/6J to generate congenic strain Construct encodes a fusion protein of the BRI protein and Aβ42 driven by the mouse prion promoter. Aβ42 is secreted through proteolytic cleavage of the protein at a furin cleavage site immediately preceding Aβ42. Transgenic Alzheimer's Disease, Cerebral Amyloid Angiopathy Detergent-insoluble amyloid-β appearing with age and cored plaques as early as 3 months in the cerebellum. Variable forebrain pathology later with extracellular Aβ plaques in the hippocampus and entorhinal/piriform cortices at 12 months. Age-associated congophillic amyloid angiopathy. No tangles or neuronal loss. On a mixed (C57/B6//C3H) background hemizygous mice have intact cognition as measured by fear conditioning at 12 months and 14-17 months despite accumulating amyloid. The Jackson Lab: Stock# 007182; Cryopreserved McGowan et al., 2005 Yes
Brown model, C9-BAC[GGGGCC]500 SJL/B6 C9orf72 Hexanucleotide repeat in C9ORF72 This transgenic mouse carries a bacterial artificial chromosome (BAC) containing exons 1 through 6 of human C9orf72 with ~500 GGGGCC repeat motifs and ~140.5 kb upstream. C9orf72: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Widespread RNA foci throughout the nervous system starting at 3 months of age, especially comprised of sense transcript. Dipeptide repeats (e.g., poly-GP) as soluble protein and insoluble aggregates. No neurodegeneration. No TDP-43 aggregation, gliosis, inflammation, or synapse loss. No overt behavioral abnormalities compared to non-Tg controls. Assessment included grip strength, Rotarod performance, and intruder test. Viable, fertile, born in Mendelian ratios. Available through Robert Brown Peters et al., 2015 Yes
Baloh/Lutz model, C9-BAC[GGGGCC]100-1000, Tg(C9orf72_3) line 112, Line F112 C57BL/6J-Tg(C9orf72_i3)112Lutzy/J C57BL/6J C9orf72 Hexanucleotide repeat in C9ORF72 This transgenic mouse carries a bacterial artificial chromosome (BAC) containing full-length human C9ORF72 sequence with ~100-1000 repeats. C9orf72: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Widespread RNA foci throughout the nervous system first assessed at 3 months of age. Soluble dipeptide repeats (e.g., poly-GP) and insoluble aggregates. No neurodegeneration. No TDP-43 aggregation, gliosis, inflammation, or obvious synapse loss. No behavioral abnormalities compared to non-Tg controls at either young age (3 months) or advanced age (18 months). Tests included: grip strength, Rotarod performance, open-field, three-chamber, and Y-maze. Viable, fertile, born in Mendelian ratios. The Jackson Lab: Stock# 023099; Live O'Rourke et al., 2015 Yes
66-repeat mice, Petrucelli’s AAV C9 model C57BL/6 C9orf72 Hexanucleotide repeat in C9ORF72 An adeno-associated viral (AAV) vector was used to deliver a sequence of 66 repeats of the hexanucleotide, GGGGCC. The virus was injected into the cerebral ventricles of P0 pups. C9orf72: Virus Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Nuclear RNA foci in neurons, dipeptide aggregates (GA, GP, and GR), cytoplasmic inclusions of phosphorylated TDP-43, neuronal loss, brain atrophy, and gliosis. Subtle behavioral deficits including anxiety-like behavior, hyperactivity, and antisocial behavior. Subtle motor impairment and failure to improve on the Rotarod. Reduced body weight in females by 6 months. Viral construct available through Leonard Petrucelli Chew et al., 2015 Yes
C9orf72 KO, 3110043O21Rik Knock-out 3110043O21Riktm1(KOMP)Mbp C57BL/6N C9orf72 The mouse 3110043O21Rik gene (homologue of human C9orf72) was inactivated by deleting a region containing exons 2-6, which includes the start codon. The targeting vector contained expression cassettes, flanked by FRT sites, for lacZ and neo as selectable markers. C9orf72: Knock-Out Frontotemporal Dementia, Amyotrophic Lateral Sclerosis Chromatolytic structures are observed with H&E staining, in gray and white matter of the spinal cord. Neurodegeneration not present. Normal sensorimotor coordination and limb strength. Reduced activity in open-field test. Spleens and lymph nodes enlarged by 1 month, size increases with age. Histology shows enlarged debris-filled cells. Available through the UC Davis Knockout Mouse Project (KOMP) Repository, gene 3110043021Rik; Cryopreserved O'Rourke et al., 2016 Yes
fPS1/fPS1Δ;Nestin-Cre (PS1 cKO) C57BL6/129 PSEN1 PS1 inactivation in neuronal progenitor cells (NPCs) and NPC-derived neurons and glia was achieved by crossing a floxed PS1 mouse with a Nestin-Cre transgenic mice. PSEN1: Conditional Knock-out Alzheimer's Disease Premature differentiation of neural progenitor cells results in reduced cells and neurons. 45 percent of late-born neurons fail to migrate to their appropriate positions in the superficial cortical layers. Gross behavior deficits. Mice are small. Premature death at 2-3 months of age. Available through Jie Shen Wines-Samuelson et al., 2005 No
APOE2-FAD, APOE2 Targeted Replacement x 5xFAD C57BL/6 APOE, APP, PSEN1 APP KM670/671NL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V APOE2 Targeted Replacement mice were crossed with the 5xFAD line. APOE: Knock-In; APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Amyloid plaques starting at 4 months and increasing with age. Gliosis and loss of synaptic proteins. In the Y maze and Morris water maze, E2FAD mice performed better than E4FAD mice, and were comparabile to E3FAD mice. 5xFAD mice are available through The Jackson Lab, Stock# 034840; Live. APOE2 Targeted Replacement mice are available through Taconic, Stock# 1547-F or 1547-M. Youmans et al., 2012 Yes
APOE3-FAD, APOE3 Targeted Replacement x 5xFAD C57BL/6 APOE, APP, PSEN1 APP KM670/671NL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V APOE3 Targeted Replacement mice were crossed with the 5xFAD line. APOE: Knock-In; APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Amyloid plaques starting at 4 months and increasing with age. Gliosis and loss of synaptic proteins. In the Y maze and Morris water maze E3FAD mice performed better than E4FAD mice, and were comparabile to E2FAD mice. 5xFAD mice are available through The Jackson Lab, Stock# 034840; Live. APOE3 Targeted Replacement mice are available through Taconic, Stock# 1548-F or 1548-M. Youmans et al., 2012 Yes
APOE4-FAD, APOE4 Targeted Replacement x 5xFAD C57BL/6 APOE, APP, PSEN1 APP KM670/671NL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V APOE4 Targeted Replacement mice were crossed with the 5xFAD line. APOE: Knock-In; APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Amyloid plaques starting at 4 months and increasing with age. Gliosis and loss of synaptic proteins.  Age-dependent learning and memory deficits in the Y maze and Morris water maze. 5xFAD mice are available through The Jackson Lab, Stock# 034840; Live. APOE4 Targeted Replacement mice are available through Taconic, Stock# 1549-F or 1549-M. Youmans et al., 2012 Yes
B6(C3H)-Sod1m1H/J C57BL/6J SOD1 D83G in SOD1 This mouse has a point mutation (A>G) in the endogenous murine Sod1 gene, resulting from exposure to the chemical mutagen N-ethyl-N-nitrosourea (ENU). The endogenous murine Sod1 promoter drives expression of the mutant protein, which carries a D83G missense mutation. SOD1: Other Amyotrophic Lateral Sclerosis Upper and lower motor neuron loss in specific regions (layer V of motor cortex and lumbar spinal cord). Gliosis in spinal cord. Denervation of hindlimb muscle. Progressive motor impairments, including tremor, gait abnormalities, decreased grip strength, and impaired Rotarod performance. Liver tumors, kyphosis (hunched back), reduced body weight, loss of SOD1 activity. The Jackson Lab: Stock# 020440; Cryopreserved Joyce et al., 2015 Yes
FUSd14 B6C3F1 FUS FUS Δ14 Recombinant adeno-associated virus (AAV) to express mutant human FUS in the brain. Viral injection into the ventricles of P0 pups. Human FUS driven by the cytomegalovirus enhancer/chicken β-actin promoter. cDNA encodes C-terminal truncation, which lacks exon 14, and thus the entire nuclear localization signal. FUS: Virus Frontotemporal Dementia, Amyotrophic Lateral Sclerosis Widespread neuronal cytoplasmic inclusions (NCIs) by 3 months of age. Inclusions were FUS-positive and often co-labeled with ubiquitin.  No overt neurodegeneration or reactive gliosis. No overt motor phenotypes at 3 months of age. Viral construct available through Thomas Kukar Verbeeck et al., 2012 Yes
Fus-dNLS, Fus-deltaNLS, Fus-ΔNLS/+ C57Bl/6 Fus FUS ΔNLS A targeting vector encoding exons 13 and 14 of FUS followed by three stop codons and a poly A signal was inserted between exons 12 and 13 of FUS. These elements are flanked by a pair of loxP sites. Insertion of this transgene results in the exclusion of exon 15 and the NLS unless Cre-recombinase is expressed to excise the transgene. Fus: Knock-In Amyotrophic Lateral Sclerosis The spinal cord exhibited FusΔNLS mislocalization, a loss of motor neurons, and ubiquitin pathology. No impairments in grip strength or rotarod performance. Irregular walking patterns and reduced hang time on inverted grid test were observed. Altered electrical activity of the gastrocnemius or tibialis anterior muscles. Unknown. Scekic-Zahirovic et al., 2016, Scekic-Zahirovic et al., 2017 Yes
B6;SJL-Tg(Prnp-FUS*R521C)3313Ejh/J Transgene injected into B6SJL oocytes. Maintained on C57BL/6, therefore subsequent generations have a higher percentage of C57BL/6. FUS FUS R521C Transgene encoding human FUS with the R521C mutation near the C-terminus. Flag-tagged construct driven by the Syrian hamster prion protein promoter. FUS: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Robust neurodegeneration in the anterior horn of the spinal cord, including about 50% loss of neurons by end stage. Prominent microgliosis and astrogliosis in the anterior horn at end stage. Very rare cytoplasmic FUS inclusions. A variety of motor impairments from a young age, including spastic paraplegia, abnormal hindlimb clasping, gait abnormalities, and impaired performance on the Rotarod. Growth retardation, muscle atrophy, DNA damage, and RNA splicing defects. Males may be sterile. The Jackson Lab: Stock# 026406; Live Qiu et al., 2014 Yes
APOE4 (line1)/APOE KO, Tg(GFAP-APOE*4)1Hol B6.Cg-Tg(GFAP-APOE_i4)1Hol Apoetm1Unc/J B6/CBA; back-crossed onto C57BL6 background APOE Transgene of human APOE4 driven by the GFAP promoter; crossed to APOE knock-out mice. APOE: Transgenic; APOE: Knock-Out Alzheimer's Disease Developing and adult mice express human APOE4 in glia and neuropil. Unknown. Mice are viable, normal in size, and do not display any gross physical or behavioral abnormalities. The Jackson Lab: Stock# 004631; Live Sun et al., 1998 No
C57B6/C3H BACE1 Transgene of human BACE1 driven by the prion protein (PrP) promoter. BACE1: Transgenic Alzheimer's Disease No evidence of Aβ deposition in single transgenic animals. Unknown. Unknown Lee et al., 2005 No
C57BL/6 J BACE1 Wild-type human BACE driven by the murine Thy1 promoter. BACE1: Transgenic Alzheimer's Disease Not observed. Unknown. Decreased levels of full-length mature APP and increased levels of C99 and C89. Human BACE mRNA 4x higher than endogenous murine BACE. Highest expression of human BACE protein in cortex and hippocampus, lowest in cerebellum. Available through Material Transfer Management at Novartis Bodendorf et al., 2002 No
Tau-ON-hFUS-P525L C57Bl/6 FUS FUS P525L Transgene encoding myc-tagged human FUS-P525L with an upstream Lox-P flanked stop sequence was inserted into the MAPT locus by homologous recombination. These mice were crossed to the Prm1-Cre line for germline recombination to remove the stop sequence, allowing transgene expression. FUS: Knock-In Amyotrophic Lateral Sclerosis Progressive loss of spinal cord motor neurons associated with muscle denervation and reduced muscle fiber diameter. Gliosis in spinal cord. Abnormal mitochondrial morphologies. Mutant FUS mislocalized to cytoplasm. Deficits in wire hang test at 360 days. Progressive denervation of hind limb muscles. Unknown. Sharma et al., 2016 Yes
PrP-hFUS Tg (Prnp-FUS)WT3Cshw/J C57Bl/6/SJL founder mice backcrossed to C57Bl/6 FUS Transgene expressing wild-type human FUS with an N-terminal HA-tag. The mouse prion protein promoter (PrP) drives transgene expression. FUS: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia FUS accumulation in the cytoplasm, including cytoplasmic inclusions in neurons of the brain and spinal cord. Degeneration of spinal motor neurons (~60% by end stage) with astrogliosis and microgliosis. Severe motor impairment, starting as tremor and gait abnormalities, and progressing to impaired performance on the Rotarod and reduced locomotion. Ultimately hindlimb paralysis and inability to lift the pelvis. Born at Mendelian ratios. Focal muscle atrophy and signs of denervation in hindlimb muscles. Most founder lines did not propagate the transgene. The Jackson Lab: Stock# 017916; Cryopreserved Mitchell et al., 2012 Yes
Tau-ON-hFUS-R512C C57Bl/6 FUS FUS R521C Transgene encoding myc-tagged human FUS-R521C with an upstream Lox-P flanked stop sequence was inserted into the MAPT locus by homologous recombination. These mice were crossed to the Prm1-Cre line for germline recombination to remove the stop sequence, allowing transgene expression. FUS: Knock-In Amyotrophic Lateral Sclerosis Progressive loss of spinal cord motor neurons associated with muscle denervation. Gliosis in spinal cord. Mutant FUS mislocalized to cytoplasm. No data. Progressive denervation of hind limb muscles. Unknown. Sharma et al., 2016 Yes
PrP-PFN1-G118V C57Bl/6 PFN1 PFN1 G118V Untagged human PFN1-G118V cDNA is expressed by the mouse prion promotor (PrP). PFN1: Transgenic Amyotrophic Lateral Sclerosis Motor neuron loss in the spinal cord associated with muscle denervation and atrophy. Gliosis in spinal cord. Loss of corticospinal neurons of the motor cortex. Aggregates of TDP-43 in spinal motor neurons. Progressive motor impairments. Minor hind limb posture changes begin at 120 days. Paralysis occurred on average by 165-210 days. Denervation and atrophy of the gastrocnemius muscle in the hindlimb. Available through Mahmoud Kiaei Fil et al., 2017 Yes
human tau B6.Cg-Mapttm1(EGFP)Klt Tg(MAPT)8cPdav/J The targeted allele was created in 129S4/SvJae-derived J1 embryonic stem cells that were subsequently injected into C57BL/6 blastocysts. The transgenic allele was generated in embryos derived from a cross between Swiss Webster and B6D2F1. Mice containing both alleles were back-crossed to C57BL/6 mice . MAPT Double mutant mice were generated by mating mice that express human tau (8c mice) (Duff et al., 2000), with tau knockout mice that have a targeted disruption of exon one of tau (Tucker et al., 2001), then back-crossed to obtain mice that are homozygous for disrupted murine MAPT while carrying the human tau transgene. MAPT: Knock-Out; MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia Age-associated tau pathology, including redistribution of tau to cell bodies and dendrites, phosphorylated tau, accumulation of aggregated paired helical filaments, and ultimately thioflavin-S positive neurofibrillary tangles. Pathology most severe in neocortex and hippocampus, and minimal in the brain stem and spinal cord. Some neuronal loss. Normal object-recognition memory and spatial learning/memory (as assessed by the Morris Water Maze) at four months, but impaired at 12 months (Polydoro et al., 2009).  General health, weight, basic reflexes, sensory responses, locomotor function, anxiety level, and gross motor function were not different from age-matched controls (Polydoro et al., 2009). The Jackson Lab: Stock# 005491; Live Andorfer et al., 2003 Yes
CaMKII-tTA/TRE-hTau-A152T C57BL/6-Tg(tetO-MAPT*A152T)L1Lms/J C59Bl/6J MAPT MAPT A152T These bigenic mice use the CaMKIIα promoter to drive expression of tetracycline transactivator (tTA) in forebrain neurons. The responder transgene is the 1N4R isoform of human tau with the A152T mutation. Expression is constitutive unless suppressed by doxycycline. MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy Tangles or dense tau inclusions not observed. Abnormal accumulations of soluble tau. Age-dependent neuronal loss was observed in the hippocampus. Age-dependent learning and memory deficits in the Morris water maze. Nest building impaired. Social interaction, anxiety, exploratory behavior, and motor functions were normal. Increase in basal synaptic activity and epileptiform spikes. Life span normal. Available as single transgenics: The Jackson Lab Stock# 028979 and Stock# 007004; Live Maeda et al., 2016 Yes
hTau40-AT, Ala152T-Tau, A152T-Tau, Tau/A152T C57BL/6 MAPT MAPT A152T Human full-length tau (hTau40) isoform 2N4R with the A152T mutation expressed under the Thy1.2 promotor is located in the ROSA26 locus. MAPT: Knock-In Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy Tangles in hippocampus, cortex, and spinal cord at 3 months with age-dependent increases. Tau hyperphosphorylation, conformation changes, and mislocalization observed. Age-dependent loss of synapses. Age-dependent learning and memory deficits in the Morris water maze. Motor functions normal. Increase in basal synaptic transmission. Available through Eva Mandelkow Decker et al., 2016, Sydow et al., 2016 Yes
Tau.P301S, hTAU[P301S], tau[P301S] Thy1-hTau.P301S (CBA.C57BL/6) CBAxC57BL/6 MAPT MAPT P301S Transgenic mice overexpressing a human tau isoform that is 383 amino acids long with four microtubule-binding repeat domains and without N-terminal inserts (4R/0N). Site-directed mutagenesis was used to introduce the P301S mutation. Transgene is under the control of the neuron-specific murine Thy-1 promoter. MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy Age-dependent hyperphosphorylation of tau and conformational changes leading to neurofibrillary tanglelike pathology in the cerebral cortex, hippocampus, brain stem, and spinal cord. Neurodegeneration, especially in the spinal cord, accompanied by astrocytosis. Early motor impairment, including abnormal clasping and rotarod deficit at 4 months, with nearly complete deficit at 5 months. Deficits progress to severe paraparesis. Disinhibition and hyperactivity at 2 to 3 months. Muscle weakness, tremor. Frequent eye inflammation. Available through reMYND Allen et al., 2002 Yes
ΔNLS4; tTA/TDP-ΔNLS, TDP-43-ΔNLS, tTA/ΔNLS B6;C3-Tg(tetO-TARDBP*)4Vle/J Transgene injected into fertilized eggs from C57BL/6J x C3HeJ. TARDBP These bigenic mice use the CAMKIIα promoter to drive expression of tetracycline transactivator (tTA) in forebrain neurons. The responder transgene is wild-type human TDP-43 minus the nuclear localization signal (NLS). Human TDP-43 is expressed constitutively unless suppressed by doxycycline. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Severe neuronal loss and gliosis in the dentate gyrus and deep cortical layers. Only very rare cytoplasmic aggregates of TDP-43 despite high levels of cytosolic protein. Degeneration of the corticospinal tract, but no lower motor neuron loss or muscle atrophy. A variety of motor, cognitive, and social deficits, including abnormal clasping response, impaired coordination on the Rotarod, decreased grip strength, impaired recognition and spatial memory, and decreased social behavior. Cognitive and motor impairments largely reversible in young mice following short-term transgene suppression. Downregulation of endogenous mouse TDP-43. No change in mortality up to 7 months of age. Mendelian ratios of offspring. The Jackson Lab: Stock# 014650; Live Igaz et al., 2011 Yes
C57BL BACE1 Transgene expressing wild-type human BACE1 driven by the mouse Thy1 promoter. BACE1: Transgenic Alzheimer's Disease Not observed. Unknown. Transgene expressed in neurons only. No change in processing of endogenous murine APP. No longer available through Michael Willem Willem et al., 2004 No
PDGF-APPSw,Ind, PDGF-hAPP695,751,770V171F, KM670/671NL, hAPPJ20, hAPP, Mucke mice B6.Cg-Tg(PDGFB-APPSwInd)20Lms/2Mmjax C57BL/6 APP APP KM670/671NL (Swedish), APP V717F (Indiana) Transgene expresses human APP with the Swedish (K670N/M671L) and Indiana (V717F) mutations under the control of the human platelet derived growth factor-β (PDGF-β) promoter. APP: Transgenic Alzheimer's Disease Age-dependent formation of Aβ plaques. Dystrophic neurites associated with plaques. No tangles. Variable cell loss. Decrease in synaptic markers and increase in complement immunoreactvity. Learning and memory deficits are age-dependent and may appear as early as 16 weeks. Hyperactivity and increased time in the open arm of the elevated plus maze than wild-type mice indicating lower levels of anxiety, but has not been universally replicated. On the C57BL/6J background hippocampal hyperexcitability was observed and cortical and hippocampal spontaneous nonconvulsive seizures. The Jackson Lab; available through the JAX MMRRC Stock# 034836; Live Mucke et al., 2000 Yes
TauP301L-JNPL3 Tg(Prnp-MAPT*P301L)JNPL3Hlmc C57BL/6, DBA/2, SW Mixed Background MAPT MAPT P301L Transgene for human MAPT (4R0N) with the P301L mutation driven by the mouse prion promoter. MAPT: Transgenic Frontotemporal Dementia, Progressive Supranuclear Palsy, Alzheimer's Disease Age and gene-dose dependent development of neurofibrillary tangles as early as 4.5 months in homozygotes and 6.5 months in heterozyotes. Tangles and Pick-body-like inclusions in the amygdala, hypothalamus, pons, medulla, and spinal cord among other areas. Neuronal loss, especially in the spinal cord. By 10 months, 90% developed motor and behavioral disturbances including limb weakness, hunched posture, decrease in grooming and vocalization. Eye irritiation, possibily due to carrying the Pde6brd1 retinal degeneration mutation carries Pde6brd1 mutation Taconic: Stock#2508 (homozygote), #1638 (heterozygote and wild-type) Lewis et al., 2000 Yes
BAC Lrrk2-G2019S, FLAG-Lrrk2-G2019S, BAC-Lrrk2-G2019S, LRRK2 G2019S BAC Tg Mouse (Yue) B6.Cg-Tg(Lrrk2*G2019S)2Yue/J A BAC construct was injected into B6C3 F1 oocytes. Founder line 2 was established and maintained by breeding to C57BL/6J inbred mice. LRRK2 LRRK2 G2019S A bacterial artificial chromosome (BAC) containing the entire mouse Lrrk2 gene was modified to include the G2019S mutation. The BAC (~240 kb) contained the murine Lrrk2 promoter region (~35 kb) and a FLAG-tag downstream of the start codon. LRRK2: Transgenic Parkinson's Disease Brain appears normal. No neuronal or cell death at 12 months. No increase in α-synuclein or ubiquitin levels or aggregation. Decreased striatal dopamine content, decreased evoked release. Apparently normal behavior. No change in activity level or motor coordination at 12 months. Mutant Lrrk2 protein purified from mouse brain had increased kinase activity. Age-dependent electrophysiological changes in the hippocampus including increased basal synaptic efficiency though a postsynaptic mechanism and decreased LTD. Available through The Jackson Lab, Stock# 012467, Live. Li et al., 2010 Yes
G2019S-LRRK2 (line 340), G2019S-LRRK2 transgenic, LRRK2 G2019S Tg Mouse (Dawson/Moore) B6;C3-Tg(PDGFB-LRRK2*G2019S)340Djmo/J Transgene introduced into C57BL/6J x C3H/HeJ embryos. Founder mice were bred with C57BL/6J mice. LRRK2 LRRK2 G2019S Transgenic mice overexpress full-length mutant human LRRK2 with the G2019S mutation. Transgene expression is driven by a hybrid CMVe-PDGFβ promoter. LRRK2: Transgenic Parkinson's Disease Age-dependent dopaminergic neuron degeneration in the substantia nigra. No reduction in striatal dopaminergic terminals or dopamine levels. No evidence of abnormal protein accumulation even at advanced ages. Abnormal mitochondria in neurons and accumulation of autophagic vacuoles. No overt behavioral abnormalities up to 24 months of age. No change in locomotor activity or prepulse inhibition of the acoustic startle reflex. No differences in body weight or survival. Available through The Jackson Laboratory, Stock# 016575, Cryopreserved. Ramonet et al., 2011 Yes
R26-LRRK2; R26-LRRK2+/+, R26-LRRK2+/+/DAT-Cre mice , ROSA26-LRRK2(R1441C), R1441C LRRK2 Tg Mouse (Moore) STOCK Gt(ROSA)26Sortm1(LRRK2*R1441C)Djmo/J R26-LRRK2 mice were generated from 129/SvJ ES cells microinjected into C57Bl/6J mouse blastocysts. Chimeras were bred with C57Bl/6J mice and maintained on a mixed genetic background (129/SvJ and C57Bl/6J). BAC-DAT-iCRE mice were maintained on a C57Bl/6J background. LRRK2 LRRK2 R1441C A cassette of full-length human LRRK2 with the R1441C mutation was targeted to the endogenous ROSA26 locus by homologous recombination. Cre-mediated excision of the transcriptional termination sequence allows for transgene expression. The Cre line expressed Cre-recombinase driven by the dopamine transporter (DAT) promoter derived from a BAC construct containing the entire mouse DAT (slc6) gene. LRRK2: Transgenic Parkinson's Disease No neurodegeneration in the brain. No proteinaceous inclusions of α-synuclein, ubiquitin, or tau. No reactive gliosis. No change in dopamine levels. Subtle morphological abnormalities in neuronal nuclei, including altered nuclear envelope. No overt behavioral differences. Activity levels and Rotarod performance are normal into advanced age. Fertile. Normal survival. No overt olfactory deficits. Available through The Jackson Laboratory, Stock# 022793, Cryopreserved. Tsika et al., 2014 Yes
WT-OX, LRRK2 WT BAC, WT LRRK2 Mouse (BAC Tg), WT LRRK2 BAC Tg Mouse (Li) FVB/N-Tg(LRRK2)1Cjli/J BAC injected into fertilized FVB zygotes. Founder mice bred with FVB/N inbred mice for many generations, and then with FVB/NJ inbred mice. LRRK2 A 188 kb human bacterial artificial chromosome (BAC) containing the entire human LRRK2 gene, with 29 kb upstream and 42 kb downstream. LRRK2: Transgenic Parkinson's Disease Overtly normal brain structure. Intact neurites. No observed behavioral differences from wild-type mice at 10 months of age. Available through The Jackson Laboratory, Stock# 009610, Live. Li et al., 2009 Yes
line 13 C57BL/6 x DBA/2F1, crossed with DBA MAPT MAPT L266V, MAPT G272V Transgene expressing human 3R tau bearing the L266V and G272V mutations under the neuronal mThy-1 promoter. MAPT: Transgenic Frontotemporal Dementia, Pick's disease, Alzheimer's Disease Accumulation of 3R tau in neurons of the cortex and hippocampus. Pick body-like tau aggregates and neuronal loss in the hippocampus and cortex. Astrogliosis, with some 3R tau in GFAP-positive astrocytes. Synapto-dendritic changes and mitochondrial pathology. Age-related memory and motor deficits as assessed by habituation to a novel environment, the Morris water maze, and the round beam test. Increased anxiety. Unknown Rockenstein et al., 2015 Yes
TASD41, Line 41, hAPPSL, hAPP-SL, AβPP751, mThy1-hAβPP751 Swe Lon (line 41), APP751SL, hAPPlon/swe line 41 , APP41 mThy1-hAβPP751 Swe Lon C57BL/6 x DBA APP APP KM670/671NL (Swedish), APP V717I (London) The transgene over-expresses the mutant human amyloid protein precursor (751 isoform), which bears both the Swedish (K670N/M671L) and the London (V717I) mutations, under the control of the murine Thy1 promoter. APP: Transgenic Alzheimer's Disease Age-dependent increases in Aβ40 and Aβ42, with Aβ42 > Aβ40. Plaques at an early age, starting at 3-6 months in the frontal cortex. At 5-7 months, size and number of plaques increased in the frontal cortex, and dense amyloid deposits appear in hippocampous, thalamus, and olfactory region. Age-associated impairment in spatial memory and learning in the water maze task and habituation in the hole-board task, with significant deficits at 6 months of age. Some gender-specific differences in open field exploration. Available through Eliezer Masliah. Also available at the CRO PsychoGenics Rockenstein et al., 2001 Yes
rNLS8, regulatable NLS B6;C3-Tg(NEFH-tTA)8Vle Tg(tetO-TARDBP*)4Vle/J NEFH-tTA mice and tetO-hTDP-43ΔNLS line 4 mice were maintained on a mixed C57BL/6J x C3HeJ background. TARDBP These bigenic mice are the progeny of NEFH-tTA transgenic mice, in which the neurofilament heavy chain promoter drives expression of tetracycline transactivator (tTA), and tetO-hTDP-43ΔNLS (line 4) mice, which express a form of human TDP-43 lacking the nuclear localization signal in a tTA-dependent manner. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Widespread cytoplasmic inclusions of TDP-43 in the brain and spinal cord. Ubiquitin-positive inclusions, loss of endogenous mouse nuclear TDP-43, cortical atrophy, motor neuron loss, astrogliosis, and NMJ denervation. A variety of motor impairments, including hindlimb clasping, fine tremor in forelimb and/or hindlimb, progressive loss of grip strength, and decline in coordinated movement and balance. Progressive decrease in body mass from a peak two weeks off dox. Atrophy of hindlimb muscles at end-stage. Premature death (median survival 10.3 weeks off dox). Available through The Jackson Lab as single transgenics: Stock# 025397 and Stock# 014650; Live. See also double transgenic Stock# 028412; Live Walker et al., 2015 Yes
dNLS-FUS, deltaNLS-FUS C57Bl/6J FUS FUS ΔNLS Transgene encoding myc-tagged human FUS with a C-terminal truncation to delete the nuclear localization signal. Expression driven by the Thy1.2 promoter. FUS: Transgenic Amyotrophic Lateral Sclerosis The motor cortex exhibited gliosis, a loss of neurons, and ΔNLS-FUS aggregates positive for ubiquitin and p62.  Progressive motor impairments by 12 weeks. Mice demonstrated tremors, limb clasping, gait abnormalities, as well as impaired performance on the Rotarod and hanging wire test. Reduced lifespan. Available through Daisuke Ito. Shiihashi et al., 2016 Yes
ΔNLS-FUS x TARDBP, deltaNLS-FUS x TAR4 C57Bl/6J FUS, TARDBP FUS ΔNLS A cross between the ΔNLS-FUS and TDP-43(WT) mice. The ΔNLS-FUS line contains a transgene expressing myc-tagged human FUS lacking the nuclear localization signal, driven by the Thy1.2 promoter. The TDP-43(WT) line contains a transgene that encodes wild-type human TARDBP, driven by the Thy-1 promoter. FUS: Transgenic; TARDBP: Transgenic Amyotrophic Lateral Sclerosis The motor cortex exhibited gliosis, a loss of neurons, and DNLS-FUS aggregates positive for ubiquitin and p62.  Progressive motor impairments by 8 weeks. Mice demonstrated tremors, limb clasping, gait abnormalities, as well as impaired performance on the Rotarod and hanging wire test. Reduced lifespan. Available through Daisuke Ito. Shiihashi et al., 2016 Yes
Origin: C57BL/6J; backcrossed with murine APOE-null mice APOE ApoE3 minigene driven by the rat neuron-specific enolase promoter. APOE: Transgenic Alzheimer's Disease Human ApoE3 protected against the age-dependent neurodegeneration seen in APOE -/- mice. Unknown. Widespread neuronal expression of ApoE in the brain. Expression of ApoE3 protected against kainic acid-induced neuronal damage (loss of synaptophysin-positive presynaptic terminals and MAP2-positive neuronal dendrites in the neocortex and hippocampus, and a disruption of neurofilament-positive axons in the hippocampus). Available through Robert Mahley Raber et al., 1998 No
Origin: C57BL/6J; backcrossed with murine ApoE-null mice APOE The ApoE4 minigene driven by the rat neuron-specific enolase promoter. APOE: Transgenic Alzheimer's Disease Not observed. NSE-ApoE4 mice showed impairments in learning a water maze task and in vertical exploratory behavior that increased with age and seen primarily in females. Neuronal ApoE expression was widespread in the brain. Expression of ApoE4 did not protect against kainic acid-induced neuronal damage. Available through Robert Mahley Raber et al., 1998 No
JU.Tg(NSE-APP751)Cordell JU (Developed by Eric Bradford at University of California, Davis) APP Transgene expresses wild-type human APP751 isoform under the control of the rat neural-specific enolase (NSE) promoter. APP: Transgenic Alzheimer's Disease Age-dependent increase in Aβ deposits and tau immunoreactivity. Learning and memory deficits are age-dependent as assessed on spontaneous alternation in a Y maze and in the water-maze task. Unknown / Extinct Quon et al., 1991 Yes
C57BL/6× DBA/2 PSEN2 PSEN2 N141I (Volga German) Transgene containing human PSEN2 carrying the N141I mutation driven by the neuron-specific enolase (NSE) promoter. PSEN2: Transgenic Alzheimer's Disease Not observed. Behavioral deficits in the water maze at 12 months in mice expressing mutatnt as well as wild-type PSEN2, including longer escape latencies than wild-type mice, but no difference in swimming speed. Expression of PSEN2 was higher in mice expressing mutant as well as wild-type PSEN2 compared to age-matched, non-transgenic mice. Alterations in levels of Aβ42, caspase-3 and Cox-2 proteins. Unknown Hwang et al., 2002 No
PARK2-Q311X, Parkin-Q311X(A), Parkin-Q311X (line A), Parkin Q311X BAC Tg Mouse (Yang) FVB/NJ-Tg(Slc6a3-PARK2*Q311X)AXwy/J The BAC was microinjected into fertilized FVB/NJ zygotes, then bred to FVB/NJ inbred mice. PRKN (parkin) Parkin Q311X Bacterial artificial chromosome (BAC)-mediated expression of mutant parkin in dopaminergic neurons. The promoter and regulatory regions of Slc6a3 (dopamine transporter) drive expression of parkin with the truncation mutation Q311X. The protein has an N-terminal Flag-tag. Two copies of the transgene integrated in tandem. PRKN (parkin): Transgenic Parkinson's Disease Degeneration of dopaminergic neurons in the substantia nigra and nerve terminals in the striatum. Reduced dopamine in the striatum. Accumulation of proteinase-K resistant α-synuclein and oxidative protein damage. Late-onset hypoactivity (about 16 months of age), other modest changes in motor behavior and coordination in tests that included traversing a beam or removing adhesive. Available through The Jackson Laboratory, Stock# 009090, Live. Lu et al., 2009 Yes
hAPP695Indiana, elan mouse, PDAPP, PD-APP C57B6 x DBA2 APP APP V717F (Indiana) A PDGF-driven human APP minigene with the V717F (Indiana) mutation. The construct contained APP introns 6-8 allowing alternative splicing of exons 7 and 8. APP: Transgenic Alzheimer's Disease Amyloid plaques in the hippocampus, cerebral cortex. Gliosis. Dystrophic neurites. Decreased synaptic and dendritic density in the hippocampus. Deficits in a variety of memory paradigms from a young age. Deficits in the radial arm maze at 3 months (before plaques), object recognition, operant learning, spatial reference memory (starting at 3-4 months), cued fear conditioning at 11 months. Alterations in sleep/wake states, thermoregulation, and motor activity.   Unknown Games et al., 1995, Rockenstein et al., 1995 Yes
APP(Swedish,Indiana), line J9, hAPPJ9, hAPPlow C57BL/6 APP APP KM670/671NL (Swedish), APP V717F (Indiana) Transgene expresses human APP with the Swedish (K670N/M671L) and Indiana (V717F) mutations under the control of the human platelet derived growth factor-β (PDGF-β) promoter. APP: Transgenic Alzheimer's Disease Amyloid plaques at 8-10 months, but not at 2-4 months when deficits in synaptic transmission are observed. Approximately 20% of mice had plaques at 5-7 months, 50% at 8-10 months, and 100% by 21-25 months. Unknown. Deficits in synaptic transmission at 2-4 months, prior to amyloid deposition. Available through Lennart Mucke Hsia et al., 1999 No
line I5 B6.Cg-Tg(PDGFB-APP)5Lms/J (C57BL/6 x DBA/2)F2 APP APP-WT driven by the human PDGF-β promoter; an APP transgene with the Indiana mutation was converted to wild-type by PCR primer modification. APP: Transgenic Alzheimer's Disease Expression of human APP in the brain especially in the neocortex and hippocampus. No plaques up to 24 months. Unknown. The Jackson Lab: Stock# 004662; Cryopreserved Mucke et al., 2000 Yes
Thy1.2-PFN1-C71G/Prp-PFN1-C71G FVB/N-Tg(Prnp-PFN1*C71G)22Zxu Tg(Thy1-PFN1*C71G)67Zxu/J FVB/NJ PFN1 PFN1 C71G Human PFN1-C71G cDNA with an N-terminal V5 tag is expressed by the human Thy1.2 promotor or mouse prion promotor (Prp). The mouse is homozygous for Thy1.2-PFN1-C71G and hemizygous for Prp-PFN1-C71G. PFN1: Multi-transgene Amyotrophic Lateral Sclerosis Motor neuron loss in the spinal cord associated with muscle denervation and atrophy. Gliosis in spinal cord. No neuronal loss in the cortex but neurodegeneration in medulla. Aggregates of PFN1, ubiquitin, and p62 form in motor neurons. Progressive motor impairments. Minor gate changes start by 4 month. Paralysis occurred on average by 7 months.Progressive decrease in body weight. Progressive decrease in body weight. Available as a triple transgenic through The Jackson Lab, Stock# 028608 Yang et al., 2016 Yes
Pink1-deficient mouse, PARK6 mouse , Pink1-/-, PINK1 G309D (PINK1-) KI Mouse (Auburger) B6;129-Pink1tm1Aub/J The vector was introduced into a 129/SvEV-derived embryonic stem cell line. Resulting chimeric mice were bred and maintained on a pure 129 background. PINK1 Pink1 G309D A targeting vector was used to introduce the G309D mutation into exon 4 at the orthologous mouse locus. A floxed neomycin cassette in the inverse orientation was inserted into intron 5 via homologous recombination. PINK1: Knock-In Parkinson's Disease No neuronal loss. No Lewy bodies or α-synuclein aggregates, but alpha-synuclein expression change in brainstem/midbrain. Low dopamine levels. Mitochondrial dysfunction (e.g., reduced ATP, reduced respiratory activity). Reduced spontaneous locomotor activity in open-field test. No difference in strength or coordination. Electrophysiological abnormalities, including altered glutamergic activity in midbrain dopaminergic neurons and early hypersynchrony in motor cortex. Medium spiny neurons in striatal slice exhibit giant GABAergic currents. Hyperactive subthalamic nucleus neurons, indicated by spontaneous bursts instead of single spikess Available through The Jackson Laboratory, Stock# 013050, Cryopreserved. Gispert et al., 2009 Yes
Pink1 KO, Pink1 -/-, Pink1 knockout mouse, PINK1 KO Mouse (Shen) B6.129S4-Pink1tm1Shn/J Congenic C57BL/6J. The construct was introduced into 129S4/SvJae-derived J1 embryonic stem cells, which were injected into C57BL/6 blastocysts. The resulting chimeric animals were crossed to generate homozygotes and then backcrossed to C57BL/6J for >7 generations. PINK1 A targeting vector containing a PGK-Neo cassette was used to disrupt exons 4 through 7 of the endogenous PINK1 gene. This creates a nonsense mutation at the beginning of exon 8; truncated RNA is degraded. PINK1: Knock-Out Parkinson's Disease Overtly normal brain structure. Normal numbers of dopaminergic neurons in the substantia nigra at 8-9 months of age. Neuronal morphology grossly intact. No data. Plasticity abnormalities. Reduced LTP and absent LTD in response to high frequency stimulation; reversed by dopamine agonists. Available through The Jackson Laboratory, Stock# 017946; Live. Kitada et al., 2007 Yes
hAPP/hTau/hPS1, PLB1(Triple) C57BL6 APP, MAPT, PSEN1 APP V717I (London), APP KM670/671NL (Swedish), PSEN1 A246E, MAPT P301L, MAPT R406W Targeted insertion of human APP and tau sequences at the HPRT site on the X chromosome, driven by mouse CaMKII-α. Human APP (isoform 770) with the Swedish and London mutations. Human tau (isoform 2N/4R, 441 amino acids) with P301L and R406W. APP/tau-expressing animals (PLB1-double) were crossed with hPS1 (A246E) transgenic mice (Borchelt et al., 1997) to generate the triple transgenic. APP: Multi-transgene; MAPT: Multi-transgene; PSEN1: Multi-transgene Alzheimer's Disease Age-related neuropathology including intraneuronal and oligomeric Aβ accumulation and hyperphosphorylated tau in the hippocampus and cortex from six months. Minimal amyloid plaques up to 21 months. Subtle tau pathology, but no overt tangles. Cortical hypometabolism with increased metabolic activity in basal forebrain and ventral midbrain by FDG-PET/CT. Cognitive deficits in recognition memory and spatial learning emerging between five and 12 months. Impairments in hippocampal plasticity. Litter size and overall health were normal. Mice spent more time awake at six months and had fragmented sleep. Quantitative EEG showed heightened delta power during wakefulness and REM sleep. Available through Bettina Platt Platt et al., 2011 Yes
hBACE1 C57BL/6J, for at least six generations BACE1 Targeted insertion of a single copy of human BACE1 at the HPRT locus on the X chromosome. Transgene expression driven by the mouse CaMKII-α promoter. BACE1: Transgenic Alzheimer's Disease Elevated extracellular multimeric Aβ, including Aβ*56 and Aβ hexamers, in the absence of plaques. At 12 months of age, astrogliosis was observed in a region- and genotype-dependent manner, especially in the dentate gyrus, hippocampal CA1, and piriform cortex. No overt tau pathology. Largely intact motor coordination and gait (Rotarod, CatWalk). Age-associated changes in multiple measures of learning and memory. Early deficits in habituation to a novel environment and semantic-like memory (three-four months). Impaired spatial learning and long-term reference (Morris water maze) and working memory (Y-maze) at six months, distinct from reduced locomotor activity and anxiety. Breeding, litter size, and overall health are normal. Reduced body weight in knock-in animals after six months of age in males and nine months in females. Available through Bettina Platt Plucińska et al., 2014 Yes
APP(Prnp), line A-2 B6.Cg-Tg(Prnp-APP)A-2Dbo/J C57BL/6 APP Transgene expresses human APP driven by the mouse prion protein promoter. APP: Transgenic Alzheimer's Disease Unknown. Unknown. Jackson Labs: Stock# 006006; Cryopreserved No
PrP-hFUS*R495X transgenic line PX78, PrP-hFUS(R495X) line PX78 B6.Cg-Tg(Prnp-FUS*R495X)78Ljh/J Construct microinjected into C57BL/6 x SJL)F2 hybrid embryos and founders bred to FVB for 4+ generations. Subsequently back-crossed at JAX to create a C57BL/6 congenic. FUS FUS R495X These mice express a mutant form of human FUS carrying a truncation mutation near the C-terminus. The transgene is driven by the mouse prion protein promoter (Prp). The mutation abrogates the nuclear localization sequence and leads to cytoplasmic mislocalization of FUS. FUS: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Cytoplasmic mislocalization of human FUS, but no cytoplasmic inclusions or signs of neuronal loss. No overt behavioral abnormalities. By 8-12 months, EMG detected hindlimb muscular abnormalities including fibrillation potentials, muscle denervation, and a reduction in the number of motor units. Congenic available through The Jackson Lab: Stock# 019728; Cryopreserved Tibshirani et al., 2015 Yes
PWT17, PrP-hFUS(WT) line PWT17 B6.Cg-Tg(Prnp-FUS)17Ljh/J Construct microinjected into C57BL/6 x SJL)F2 hybrid embryos and founders bred to FVB for 4+ generations. Subsequently back-crossed at JAX to create a C57BL/6 congenic. FUS These mice overexpress wild-type human FUS. The transgene is driven by the mouse prion protein promoter (PrP). FUS: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia No overt neuropathology. Predominantly nuclear FUS. No inclusions or over neuronal loss. No overt behavioral abnormalities prior to becoming moribund around 203 days of age. Unexplained premature lethality about 203 days of age, proceeded by less than a week of ill-health. Congenic available through The Jackson Lab: Stock #020783; Cryopreserved Tibshirani et al., 2015 Yes
FVB/N PSEN1 PSEN1 A246E Transgene human PSEN1 with the A246E mutation driven by the mouse Thy1 promoter. PSEN1: Transgenic Alzheimer's Disease Histologically normal up to 2 years old by hematoxylin-eosin, silver, and thioflavin-S staining. Learning and spatial memory were unaffected in the water maze test. Neither the escape latency nor escape pathway was different from PSEN1 wild-type mice at 1 and 9 months of age. Mice are more sensitive to kainic acid displaying greater KA-induced seizure activity and neuronal damage. LTP induced by a strong stimulus was not altered, but a weak stimulation at synapses between Schaeffer’s collaterals and CA1 pyramidal neurons elicited LTP only in mutant mice. No longer available through Paul van Dun Schneider et al., 2001 No
PS1 conditional KO, PSEN1 conditional KO fPS1/fPS1;αCaMKII-Cre CaM-Cre tg mice were generated in C57BL/6J x CBA hybrid, and then back-crossed several generations to C57BL/6J. The floxed PS1 mouse was generated in C57BL/6J and 129/Sv hybrid. PSEN1 PS1 conditional KO mice with selective deletion of PSEN1 in excitatory neurons of the forebrain beginning about 1 month of age post-natally were generated by crossing a floxed PS1 mouse with a CamKII-Cre transgenic mouse. PSEN1: Conditional Knock-out Alzheimer's Disease Reduction in Aβ40 and Aβ42 peptides; accumulation of APP C-terminal fragments. Subtle but significant deficits in long-term spatial memory in the Morris water maze. Available through Jie Shen Yu et al., 2001 Yes
PSEN1(M146L), PS1 (M146L) line 5.1 B6/D2/Swe/SJL mixed background PSEN1 PSEN1 M146L (A>C) Transgene containing human PSEN1 with the M146L mutation driven by the rat PDGF-β promoter. PSEN1: Transgenic Alzheimer's Disease No abnormal pathology up to 2.5 years. Elevated Aβ2(43); no effect on Aβ40. Altered mitochondrial activity. Disregulation of calcium homeostasis. No difference from wild-type mice in the “Y” maze (alternation performance or activity) at 12-14 weeks. Elevated PSEN1 expression (2-3 fold). Medium and late after hyperpolarizations in CA3 pyramidal cells were larger compared with wild-type mice. Larger calcium responses to depolarization. Stronger synaptic potentiation of the CA3 to CA1 projection. Available through the Technology Transfer Office, Patents & Licensing, University of South Florida. Also available at the CRO PsychoGenics Duff et al., 1996 No
PSEN1(M146V) (line 8.9) Swiss Webster x B6D2F1 PSEN1 PSEN1 M146V Transgene containing human PSEN1 with the M146V mutation driven by the rat PDGF-β promoter. PSEN1: Transgenic Alzheimer's Disease No abnormal neuropathology up to 2.5 years. Elevated Aβ42(43). Altered mitochondrial activity and disregulation of calcium homeostasis. Unknown. Medium and late after hyperpolarizations in CA3 pyramidal cells were larger compared with nontransgenic or mice transgenic for wild-type PSEN1. Available through the Technology Transfer Office, Patents & Licensing, University of South Florida Duff et al., 1996 No
PS-1 P264L knock-in R1 line of the ES cells (129 mouse strain) PSEN1 PSEN1 P264L An exon replacement strategy was used to generate mouse lines carrying a targeted mutation in their endogenous presenilin-1 gene. A proline-to-leucine substitution was targeted to codon 264 in exon 8 by homologous recombination in embryonic stem (ES) cells. Cre-lox system to remove the neomycin selection cassette from the targeted gene. PSEN1: Knock-In Alzheimer's Disease Not observed. Unknown. Unknown Siman et al., 2000 No
B6.PS2APP, TG B6.PS2APP mice (line B6.152H) Tg(Thy1-APPSwe,Prnp-PSEN2*N141I)152HLaoz C57BL/6 APP, PSEN2 APP KM670/671NL (Swedish), PSEN2 N141I (Volga German) Coinjection of two transgenes into C57/Bl/6 zygotes: Human PSEN2 gene with the N141I mutation driven by the mouse prion protein promoter and human APP751 with the Swedish mutation driven by the Thy1.2 promoter. APP: Transgenic; PSEN2: Transgenic Alzheimer's Disease Age-associated development of plaques: none at 3 months, overt Aβ deposition in the brain at approximately 6 months, with heavy plaque load in the hippocampus, frontal cortex, and subiculum at 10 months. Aβ deposits in blood vessels were sporadic, mainly in large vessels. Cerebral amyloid deposits correlate with levels of the human APP transcript at 12 months. Cognitive impariment detected by the Morris water maze at 8 and 12 months of age, but not at 3 months. Decreased survival of newborn neurons in the dentate gyrus at about 4 months. Reduced endoplasmic reticulum Ca2+ and calcium dysregulation. A strong increase in LTP and post-tetanic potentiation (PTP) in hippocampal slices of 10 month old animals compared to wild-type mice. Decreased perfusion in the occipital cortex at all ages tested (10-17 months). Available through Laurence Ozmen Ozmen et al., 2009 Yes
PS2(N141I) x APPswe , hPS2(N141I) x hAPPswe Tg(Thy1-APPSwe)71Jgr x Tg(Prnp-PSEN2*N141I)30Jgr C57BL/6, DLB/2, crossed to C57BL/6 APP, PSEN2 APP KM670/671NL (Swedish), PSEN2 N141I (Volga German) Double transgenics created by crossing APPSwe mice (transgene containing the 751 isoform of human APP with the Swedish mutation driven by the Thy1.2 promoter) with PS2(N141I) mice (tansgene containing human PSEN2 with the N141I mutation driven by the mouse prion protein promoter). APP: Transgenic; PSEN2: Transgenic Alzheimer's Disease Rare amyloid deposits at 5 months, with consistent deposits in the subiculum and frontolateral cortices by 9 months. Plaques increase in number and distribution with time, spreading throughout the neocortex and hippocampus as well as the amygdala and thalamic and pontine nuclei. The distribution and abundance of activated microglia and astrocytes correlate with Aβ deposition. Mice develop age-associated cognitive impairment from 8 months with impaired acquisition of spatial learning in the water maze. More insoluble Aβ40 and Aβ42 than age-matched APPSwe mice at 16-18 months. Loss of metabotropic glutamate receptors (mGlu2) in certain brain regions of aged mice as demonstrated by autoradiography. Available through Laurence Ozmen Richards et al., 2003 Yes
Prp-huPS2(N141I), PS2-N141I (line 30), hPS2mut Tg(Prnp-PSEN2*N141I)30Jgr Originally generated in a B6.D2 background, then crossed into C57BL/6J. PSEN2 PSEN2 N141I (Volga German) Human PSEN2 gene with the N141I mutation driven by the mouse prion protein promoter. PSEN2: Transgenic Alzheimer's Disease Unknown. Unknown. Ubiquitous expression of mutant transgene. Brain homogenate from 2 week-old mice had PSEN levels 1.8-2.2 fold higher than wild-type mice. Disrupted Ca2+ homeostasis, similar to that of double transgenic PS2APP mice, including a reduction in endoplasmic reticulum Ca2+ content in cultured neurons and a generally decreased response to metabotropic agonists. Available through Laurence Ozmen Richards et al., 2003 No
PS1 + APP, PSAPP, APP/PS1, APP/PS1 double transgenic B6/D2/Swe/SJL mixed background APP, PSEN1 APP KM670/671NL (Swedish), PSEN1 M146L (A>C) These double transgenic mice were generated by crossing mice overexpressing human APP with the Swedish mutation driven by the hamster prion protein gene promoter (the Tg2576 model) with mice overexpressing human PSEN1 with the M146L mutation driven by the PDGF-β promoter (PSEN1(M146L), line 5.1). The two transgenes segregate independently. APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Aβ accumulates in the cerebral cortex and hippocampus starting ~6 months and increasing with age. Other regions affected later. Deposition occurs in white matter,  cerebrovasculature, and grey matter in the form of diffuse and fibrillar plaques. Fibrillar deposits are associated with dystrophic neurites and GFAP-positive astrocytes at ~ 6 months with later microglial activation. Progressive impairment between 5–7 and 15–17 months in some tests of cognitive performance, but not others. No change in anxiety levels. Selective increase in brain Aβ42(43) in the double transgenics (41% increase at 6 weeks) compared to Tg2576 single transgenic, which had unchanged Aβ40 and Aβ42(43) at this age. Tg2576: Taconic (Stock #001349) and Charles River; PS1(M146L): University of South Florida Technology Transfer Office; double transgenic: also available at the CRO PsychoGenics Holcomb et al., 1998 Yes
PS1/PS2 cDKO, PSEN1/PSEN2 conditional double knock-out fPS1/fPS1;αCaMKII-Cre;PS2-/- C57BL6/129 hybrid PSEN1, PSEN2 To generate forebrain-specific conditional double knockout mice lacking both PS1 and PS2 (PS cDKO) mice, floxed PS1 (fPS1), αCaMKII-Cre transgenic mice and PS2-/- mice were crossed together to obtain fPS1/fPS1;αCaMKII-Cre;PS2-/- mice. PSEN1: Conditional Knock-out; PSEN2: Knock-Out Alzheimer's Disease At 2 months the number of apoptotic neurons is elevated about 8-fold. By 6 months, about 18 percent of of cortical neurons are lost. Up-regulation of inflammatory markers and progressive astrogliosis and microgliosis in the neocortex and hippocampus. Impairments in hippocampal learning and memory as indicated by Morris water maze and contextual fear conditioning evident by 2 months and worsens with age. Increased neurogenesis in the dentate gyrus. Available through Jie Shen Saura et al., 2004 Yes
PS1 conditional KO B6;129P-Psen1tm1Vln/J Origin: 129P2/OlaHsd; backcrossed to C57BL/6 PSEN1 A targeting vector containing a neomycin resistance gene was inserted downstream of exon 7 of PSEN1; loxP sites were inserted on both sides of exon 7 and downstream of the neomycin resistance gene. PSEN1: Knock-Out Alzheimer's Disease No morphological abnormalities. When crossed with Cre recombinase driven by Thy1, brain levels of Aβ40 and Aβ42 decrease and C-terminal fragments of APP accumulate. When crossed with Cre recombinase driven by Thy1, no cognitive deficit in an object recognition task. When crossed with Cre recombinase driven by Thy1, LTP induction is slightly altered. The Jackson Lab: Stock# 007605; Cryopreserved Dewachter et al., 2002 No
PS1 -/-, PSEN1 null, Psen1tm1Shn, PS1 null B6.129-Psen1tm1Shn/J C57BL/6 PSEN1 A targeting construct containing a neomycin cassette was used to disrupt exons 2 and 3 of the endogenous mouse PS1 gene. PSEN1: Knock-Out Alzheimer's Disease Impaired neurogenesis. Massive neuronal loss. Hemorrhages in the CNS. Unknown. Homozygous mice die shortly after birth; heterozygous mutants are viable and fertile. Gross skeletal malformations. The Jackson Lab: Stock# 003615; Cryopreserved Shen et al., 1997 No
PS1M146V KI B6.129-Psen1tm1Mpm/J C57BL/6 PSEN1 PSEN1 M146V Point mutations were introduced into exon 5 of the endogenous mouse PSEN1 gene altering the codons corresponding to amino acids 145 and 146 from isoleucine and methionine to valine and valine, respectively. The targeting vector contained a lox-P flanked neomycin resistance cassette and herpes simplex virus thymidine kinase genes. PSEN1: Knock-In Alzheimer's Disease Hypersensitive to kainate-induced degeneration and death of CA3, CA1 and hilar neurons. Cultured hippocampal neurons have increased vulnerability to death induced by glutamate. Disrupted calcium homeostasis. Increased oxidative stress and mitochondrial dysfunction. Unknown. Mice are viable, fertile, and normal in size. No gross physical or behavioral abnormalities. The Jackson Lab: Stock# 004193; Cryopreserved Guo et al., 1999 No
line 13, PS1(P117L) Mixed C57BL/6 and DBA/2J PSEN1 PSEN1 P117L Transgene of human PSEN1 with the P117L mutation driven by the neuron specific enolase (NSE) promoter. PSEN1: Transgenic Alzheimer's Disease No plaques or diffuse amyloid deposits at 2-3 months. Elevated generation of Aβ42. Unknown. Express human PSEN1 at 2-3x the level of endogenous murine PSEN1. Impaired neurogenesis in the hippocampus. No longer available Wen et al., 2002 No
PS1(WT), PSEN1 (wild-type) Mixed C57BL/6J, DBA/2J PSEN1 Human wild-type PSEN1 driven by neuron-specific enolase (NSE). PSEN1: Transgenic Alzheimer's Disease No pathological changes have been observed in these mice. Unknown. No longer available Wen et al., 2002 No
line G9, H163R mutant PS-1 YAC, B6-G9, PS1-YAC B6.129S4-Tg(PSEN1H163R)G9Btla/J Origin: 129S4/SvJae, backcrossed to C57BL/6 PSEN1 PSEN1 H163R A 1000 kb YAC transgene (788H12) containing the entire human PSEN1 gene with the H163R mutation. Transgene also has ~550 kb of upstream and 350 kb of downstream flanking sequences. PSEN1: Transgenic Alzheimer's Disease Elevated Aβ42 in the brain and plasma. Higher levels and earlier Aβ deposition when crossed with APP YAC line R1.40. Unknown. Alternatively spliced human PSEN1 transcripts. The Jackson Lab: Stock# 006469; Cryopreserved Lamb et al., 1999 No
PS2 -/-, PSEN2 null, PSEN KO, PS2 null B6.129P-Psen2tm1Bdes/J 129P2/OlaHsd derived embryonic stem cells injected into C57BL/6 blastocysts; resulting chimeric mice backcrossed to C57BL/6J PSEN2 A targeting vector containing a hygromycin resistance gene driven by the phosphoglycerate kinase promoter was used to disrupt exon 5 of PSEN2 by introducing a frame shift between exons 4 and 6. PSEN2: Knock-Out Alzheimer's Disease No gross brain abnormalities or astrogliosis. Unknown. Alveolar wall thickening, pulmonary fibrosis, mild hemorrhage in the lungs. The Jackson Lab: Stock# 005617; Cryopreserved Herreman et al., 1999 No
APPNLI 129S6FVB F1 APP APP KM670/671NL (Swedish), APP V717I (London) These are bigenic mice with the CAMKII-α promoter driving expression of tetracycline transactivator (tTa) in excitatory neurons in the forebrain, and a responder transgene consisting of mutant human APP (isoform 695) carrying the Swedish and London mutations. The expression of the transgene is constitutive until suppressed by doxycycline. APP: Transgenic Alzheimer's Disease Age-associated pathology in the cerebral cortex and hippocampus starting at 8 and 10½-12½ months of age, respectively. Gliosis and hyperphosphorylated tau in the vicinity of dense-core plaques. Fibrillar oligomeric species, e.g., Aβ dimers. No transgene-related deficits seen in Morris water maze (4, 12, 21, 24, months of age) or fixed consecutive-number (23 months of age) tests. Reduced body weight at 24-27 months relative to non-Tg littermates and those expressing only tTA. Available through Karen Ashe Liu et al., 2015 Yes
neuropsin-tTA x FVB-Tg(tetO-tauP301L)4510 4510 mice are on an FVB background. Neuropsin-tTA mice are on a C57BL/6 background. MAPT MAPT P301L Bigenic mice made by crossing an activator line, neuropsin-tTA, with a responder line, Tg(tetO-tauP301L)4510. The neuropsin promoter drives the tetracycline transactivator (tTA) transgene preferentially in a subset of entorhinal neurons. tTA drives expression of human tau (isoform 4R0N) with the P301L mutation. Transgene expression in bigenic mice is constitutive until suppressed by doxycycline. MAPT: Transgenic Frontotemporal Dementia, Alzheimer's Disease Propagating tau pathology starting in the entorhinal cortex and spreading to regions functionally connected to the EC (e.g., dentate gyrus). Neurodegeneration and axonal degeneration, first in EC and parasubiculum. Gliosis and synaptic loss. Subtle cognitive deficit in contextual fear conditioning, but not in the radial arm maze, at 16 months. Mild specific deficit in locomotor activity in the open field test. No apparent change in anxiety as assessed by the open field test. Reduced Arc induction in the hippocampus after contextual fear conditioning. Subtle differences in basal synaptic transmission with enhanced axonal excitability. de Calignon et al., 2012 Yes
rTg4510, Tg(tetO-TauP301L)4510, Tau P301L FVB-Tg(tetO-MAPT*P301L)#Kha/JlwsJ, STOCK Tg(Camk2a-tTA)1Mmay Tg(tetO-MAPT*P301L)#Kha/J FVB/N (Double tg also has B6) MAPT MAPT P301L Transgene has human four-repeat MAPT lacking the amino terminal sequence (4R/0N) with the P301L mutation. Expression is driven by a tetracycline operator (tetO) upstream of a cytomegalovirus minimal promoter and contains exons 2-3 of the mouse prion protein gene (Prnp) untranslated sequence. MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia Argyrophilic tangle-like inclusions in cortex by 4 months and in hippocampus by 5.5 months. Decreased CA1 neurons (~60 percent) by 5.5 months. Gross forebrain atrophy by 10 months. The number of CA1 neurons stabilized after a brief (six to eight week) suppression of transgenic tau. No significant abnormalities at 1.3 months in the Morris Water Maze. Spatial memory impairments by 2.5 to 4 months. No significant motor impairment up to 6 months of age. When the transgene was suppressed with dox at 2.5 months, spatial memory improved. Homozygous mice are not viable. Single transgenic: The Jackson Lab: Stock# 015815; Live. Double transgenic: The Jackson Lab: Stock# 024854; Live. Also available at the CRO PsychoGenics Santacruz et al., 2005 Yes
Tau R406W-Prp C57BL6 x C3H, maintained in B6C3 background MAPT MAPT R406W Human tau with the R406W mutation driven by the mouse prion protein promoter. MAPT: Transgenic Frontotemporal Dementia Age-dependent increase in tau. Neurofibrillary-tangle-like pathology (filamentous intraneuronal tau aggregates), especially in the hippocampus. Neurodegeneration. Extensive gliosis in the brain and spinal cord. Progressive motor weakness with advancing age, as demonstrated by dystonic movements of the hindlimbs when lifted by the tail. Altered microtubule binding and slow axonal transport of tau. Reduced lifespan. Unknown Zhang et al., 2004 No
SAMP8, SAMP-8, SAM-P/8, SAM-P8 AKR/J, suspected outbreeding to unknown line One of several related strains developed from an AKR/J inbred line with a spontaneous accelerated aging phenotype. Spontaneous Alzheimer's Disease Age-associated increase in hippocampal Aβ from 4 to 12 months, but no plaque-like structures by Congo red or thioflavine S. Spongiform degeneration: vacuoles of various size in the neuropil in the brain stem. Microglial cell proliferation. Degeneration of dopamine neurons in the substantia nigra and noradrenaline neurons in the locus coeruleus. Age-associated behavioral impairments including learning and memory difficulties, emotional disorders (reduced anxiety-like behavior and depressive behavior) and altered circadian rhythms of spontaneous motor activity and drinking behaviours. Envigo (formerly Harlan): SAMP8-TaHsd Yagi et al., 1988 No
line 29, SOD1 (G37R) (hybrid background), G37R(29) SOD1, SOD1 G37R C57BL/6J x C3H/HeJ)F2 SOD1 SOD1 G37R Transgene carrying a 12kb DNA fragment encoding human SOD1 with the G37R mutation. Transgene driven by the human SOD1 promoter. SOD1: Transgenic Amyotrophic Lateral Sclerosis Degeneration of motor neurons in the spinal cord and brainstem characterized by extensive vacuolization. Astrogliosis. Wallerian degeneration of large myelinated axons. No overt upper motor neuron loss. Progressive motor impairment, beginning with reduced spontaneous movement, then tremors, limb weakness, poor grooming, and muscle wasting. Eventual paralysis of hindlimbs. Elevated dismutase activity in the brain and spinal cord (~7-fold). Unknown Wong et al., 1995 Yes
SOD1 (G85R) (line 148) Transgene injected into hybrid (C57BL/6J x C3H/HeJ)F2 embryos. SOD1 These transgenic mice express human SOD1 with the G85R substitution. 12 kb DNA sequence under the control of the human promoter and regulatory elements. SOD1: Transgenic Amyotrophic Lateral Sclerosis Degeneration of lower motor neurons, especially large-caliber axons, but also loss of motor neurons in the ventral horn. Extensive glial pathology in the spinal cord, including astrogliosis and microgliosis. Abundant SOD1 inclusions in astrocytes. Progressive motor impairment generally starting around 8 months of age with reduced grip strength in one hindlimb, rapidly spreading to other limbs and leading to paralysis. Unknown status of the hybrid line. A congenic line is available through The Jackson Lab: Stock# 008248; Cryopreserved Bruijn et al., 1997 Yes
G1H, High-copy SOD1-G93A, B6SJL SOD1-G93A, Tg(hSOD1-G93A)1GUR mice, Gurney mice B6SJL-Tg(G93A-SOD1)1Gur/J C57Bl/6/SJL. SOD1 SOD1 G93A These transgenic mice express multiple copies of human SOD1 bearing the missense mutation G93A randomly integrated into chromosome 12 of the mouse. SOD1: Transgenic Amyotrophic Lateral Sclerosis Neuronal loss in the spinal cord (~50% loss in cervical and lumbar segments by end stage). Degeneration of upper motor neurons and brainstem nuclei. Swollen neurites, Gallyas silver-positive aggregates, vacuoles, and neuritic spheroids. Gliosis. Axonal degeneration and denervation of NMJ. Progressive motor impairment that starts as a shaking tremor. Proximal muscle weakness along with muscle atrophy, eventually leading to paralysis and death. Weight loss. The mutant SOD1 retains enzymatic activity. The Jackson Lab: Stock# 002726; Live Gurney et al., 1994, Chiu et al., 1995 Yes
hm2 α-SYN-39, HM2, hm2 α-SYN, human doubly mutated α-synuclein, A30P/A53T aSyn Mouse (Tg), A30P/A53T aSyn Tg Mouse (Richfield), alpha-synuclein A30P/A53T Mouse (Tg) C57BL/6J-Tg(Th-SNCA*A30P*A53T)39Eric/J Transgene injected into C57/BL6 oocytes, then bred to C57/BL6J. SNCA SNCA A30P, SNCA A53T This model expresses a transgene encoding human α-synuclein with two mutations (A30P and A53T) driven by 9kb rat tyrosine hydroxylase (TH) promoter. SNCA: Transgenic Parkinson's Disease No dopaminergic cell loss. No α-synuclein inclusions. Morphological abnormalities in the dopaminergic system, including axonal and dendritic abnormalities, reduced dopamine concentration in the striatum. More active as young adults, then hypoactive compared to non-Tg. Also reduced motor coordination in old age as measured by the time to right from an inverted wire screen. No weight differences compared to non-Tg. Available through The Jackson Laboratory, Stock# 008239, Live. Richfield et al., 2002 Yes
G2-3(A53T), PrPsynA53T, A53TαS Tg mice (line G2-3), MoPrP-Huα-Syn(A53T), Hualpha-Syn(A53T), A53T aSyn Tg Mouse (Lee) , alpha-synuclein A53T Mouse (Tg) B6.Cg-Tg(Prnp-SNCA*A53T)23Mkle/J Established as C3H/HeJ x C57BL6/J hybrids, then maintained by backcrossing to C57Bl6/J. SNCA SNCA A53T Transgene comprising human α-synuclein with the A53T mutation was inserted downstream of the mouse prion protein (PrP) promoter. SNCA: Transgenic Parkinson's Disease No overt neuronal loss. No change in striatal dopamine levels. Region-specific neuronal accumulation of fibrillar α-synuclein, ubiquitin, and neurofilament-H, and accompanying astrocytosis. Early hyperactivity followed by severe motor impairment, manifesting as wobbling, posturing, decreased spontaneous locomotor behavior, inability to navigate the Rotarod, and ultimately paralysis and death. Premature death. Available through The Jackson Laboratory, Stock# 006823, Live. Lee et al., 2002 Yes
PAC-Tg(SNCA-A53T) +/+; Snca-/-, dbl-PAC-Tg(SNCAA53T);Snca-/- , A53T aSyn Tg Mouse (Nussbaum), Alpha-synuclein A53T Mouse (Tg) on SNCA KO FVB;129S6-Sncatm1Nbm Tg(SNCA*A53T)1Nbm Tg(SNCA*A53T)2Nbm/J The PAC transgene was injected into FVB/N oocytes and founder mice bred to FVB/N. The knockout mice were made in a 129S6/SvEvTac background. SNCA SNCA A53T In this double-transgenic model, one parental line expresses mutant human α-synuclein (A53T mutation) via a 146 kb P1 artificial chromosome (PAC) containing full-length human SNCA gene and 34 kb upstream sequence. The other line is an Snca knockout line generated by replacing exons 4 and 5 with a neomycin resistance cassette. SNCA: Transgenic; SNCA: Knock-Out Parkinson's Disease No loss of dopaminergic neurons in the substantia nigra by 18 months of age. Rare dystrophic synapses in the hippocampus at advanced age, but no Lewy body-like pathology or α-synuclein aggregation in the brain. No change in striatal dopamine concentration. Impaired performance on the Rotarod and reduced spontaneous locomotor activity in open-field test. Gastrointestinal dysfunction (e.g., reduced fecal mass, reduced colonic motility, prolonged whole-gut transit time). α-synuclein–positive aggregates in enteric nervous system. No difference in body weight. No olfactory deficits. No difference in autonomic regulation of heart rate. Available through The Jackson Laboratory, Stock #010799; Live. Kuo et al., 2010, Cabin et al., 2002 Yes
Snca KO, Snca -/-, Snca KO Mouse (Nussbaum), Alpha-synuclein KO Mouse Inbred 129/SvEvTac background. SNCA The mouse Snca gene was disrupted using a targeting vector that replaced exons 4 and 5 with the neomycin resistance gene. SNCA: Knock-Out Parkinson's Disease No gross brain abnormalities. Electron microscopy revealed synaptic vesicle abnormalities in hippocampal neurons, i.e., fewer vesicles in the reserve pool. Behavior is largely normal. Normal performance on the Rotarod. Subtle differences in locomotor activity (e.g., less rearing) but normal overall distance travelled. Learning and memory appear intact. Possible anxiety-like phenotype. Microglial abnormalities. Reduced cardiolipin content in the brain. Some mitochondrial abnormalities. Unknown. Cabin et al., 2002 Yes
Sncaflox(neo), SNCAflox delta neo, Snca conditional knockout, SNCA KO Mouse (Buchman), Alpha-synuclein KO Mouse (Conditional) B6(Cg)-Sncatm1.1Vlb/J C57BL/6J SNCA A targeting vector containing a FRT site-flanked neomysin cassette and a loxP site was inserted downstream of exon 2 and another loxP site was inserted upstream of exon 2. Flp-mediated recombination removed the FRT-flanked neo cassette, leaving exon 2 floxed. When bred to Cre-expressing mice, the resulting offspring have the first coding exon deleted in Cre-expressing tissues. SNCA: Conditional Knock-out Parkinson's Disease No data. No data. Available through The Jackson Laboratory, Stock #025636, Live. Ninkina et al., 2015 Yes
B6.Cg-Tg(Prnp-TARDBP*A315T)95Balo/J C57BL/6J x CBA mice backcrossed to C57BL/6J. TARDBP TARDBP A315T This transgenic mouse expresses full-length human TARDBP with an N-terminal Flag tag and the A315T mutation. The transgene is driven by the mouse prion protein (PrP) promoter. TARDBP: Transgenic Amyotrophic Lateral Sclerosis Minimal motor neuron loss in the spinal cord and cortex (but see Espejo-Porras et al., 2015 and Zhang et al., 2016). Ubiquitin-positive aggregates in upper and lower motor neurons. Rare TDP-43 aggregates. Astrocytosis in spinal cord and cortical layer V. Hyperexcitability of somatostatin interneurons. Axonal degeneration and ~ 20% loss of NMJ innervation (gel diet). Variable. Gait abnormalities, and impaired performance on the Rotarod. Also deficits in radial arm water maze, not due to deficits in swimming speed. Behavior potentially confounded by gut phenotype.   Severe dysfunction in the intestinal tract involving degeneration of neurons in the colon resulting in reduced motility though the ileocaecal area. GI obstruction is the likely cause of death unless the diet is modified with soft food or gel diet. The Jackson Lab: Stock# 010700; Live Wegorzewska et al., 2009, Hatzipetros et al., 2014 Yes
Baloh’s TDP-43, C57BL/6-CBA TDP-43 A315T The Prp-TDP43A315T transgene was introduced into oocytes from C57BL/6J x CBA mice. TARDBP TARDBP A315T Transgene encodes full-length, human, mutant TARDBP with the A315T mutation and an N-terminal Flag tag. The mouse prion protein (PrP) promoter drives transgene expression. TARDBP: Transgenic Amyotrophic Lateral Sclerosis Upper and lower motor neuron loss. Cytoplasmic aggregates of ubiquitinated proteins in motor neurons. Cortical gliosis. No cytoplasmic aggregates of TDP-43. Gait abnormalities around three months, developing into a characteristic “swimming gait” by four to five months. Born at normal Mendelian ratios. Grossly normal up to three months. Muscle pathology at end-stage, including atrophic muscle fibers. Generally milder phenotypes in females. No longer available on a C57BL/6J x CBA background Wegorzewska et al., 2009 Yes
thy1-APPswe Transgene injected into C57BL/6 x C3H oocytes, some backcrossing to C57BL/6 APP APP KM670/671NL (Swedish) Transgene expresses human APP (isoform 695) harboring the Swedish mutation, driven by the murine Thy-1 promoter. APP: Transgenic Alzheimer's Disease Age-related accumulation of Aβ in the hippocampus and cortex leading to plaque deposition by 12 months of age. Early gliosis and dystrophic neurites, not limited to the vicinity around plaques. Changes in synaptic morphology and number, along with increased number of lysosomes. Deficits in spatial memory prior to Aβ deposition, including deficits in the Morris water maze by 6 months Deficits in spontaneous alternation behavior in the Y maze by 12 months. No deficit in fear conditioning. No differences in body temperature, locomotor activity, or Rotarod performance, relative to non-Tg controls. Unknown Richardson et al., 2003 Yes
TAS10 x TPM, APPswe x PS1.M1466V, TAS/TPM TAS10 transgene originally injected into C57BL/6 x C3H oocytes, with some backcrossing to C57BL/6. TPM generated on pure C57BL/6 background. APP, PSEN1 APP KM670/671NL (Swedish), PSEN1 M146V This is a double transgenic model generated by crossing TAS10 mice (an APP transgenic line expressing human APP695 with the Swedish mutation) with TPM mice (a PSEN1 transgenic expressing human PSEN1 with the M146V mutation). Both transgenes are driven by the murine Thy-1 promoter. APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Aβ deposits beginning at 3 months of age, with fibrillar plaques by 6 months in the cerebral cortex and hippocampus. Some vascular amyloid. Plaques surrounded by dystrophic neurites and reactive glia. No tangles or neuronal loss. Female mice have more rapid and severe amyloid pathology. Age-dependent impairment in object recognition memory starting around 6 months of age.  Unknown Howlett et al., 2004 Yes
Tau(WT) transgenic (line 264) B6C3F1 embryos, backcrossed to C57BL/6 MAPT This transgenic mouse expresses 3-repeat (3R) and 4-repeat (4R) isoforms of wild-type human tau. The minigene, driven by the mouse CAMKIIα promoter, includes intronic sequences flanking exon 10, allowing for physiological splicing of exon 10. MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy No overt neuropathology even at the advanced age of 24 months. Comparable to non-Tg mice in Morris water maze tasks at 4 and 6 months of age. Available through Hiroshi Mori and Takami Tomiyama Umeda et al., 2013 No
C57BL/6 (75%) and 129/Ola (25%). MAPT A fragment of human tau (187-441 a.a.) expressed under control of the human tau promotor was inserted at the Hprt locus. MAPT: Transgenic Progressive Supranuclear Palsy, Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy Progressive tau pathology in the hippocampus, including abnormally phosphorylated and misfolded tau, mislocalized tau, and tangle-like structures. Dystrophic neurites. Impaired spatial learning and memory in the Morris water maze. Early motor impairments, including abnormal limb clasping, Rotarod deficits and decreased grip strength. Muscle fibers in the quadriceps and latissimus muscles appeared to be degenerative/regenerative. Progressive spine curvature. Unknown. Bondulich et al., 2016 Yes
B6.Cg-Tg(Thy-MAPT*)2652Gds C57BL/6J MAPT This transgenic mouse overexpresses wild-type human tau (1N4R). The Thy1.2 promoter drives high levels of transgene expression in the CNS. MAPT: Transgenic Frontotemporal Dementia, Other Tauopathy, Alzheimer's Disease Extensive pretangle pathology throughout the brain (e.g. phospho- tau) but no mature neurofibrillary tangles and only mild oligomeric tau, restricted to the CA1 region of the hippocampus. Dystrophic neurites and axonal pathology (spheroids). No overt neuronal loss. Motor deficits develop with age, including decreased grip strength and impaired Rotarod performance. Cognitive deficits, indicative of impaired spatial learning and memory, as assessed by the Barnes maze. Homozygous mice have reduced body weight, reduced fertility, and premature death. Some homozygous mice also exhibit seizure activity. The MMRRC Stock# MMRRC:036717 Wheeler et al., 2015 Yes
Tau 10 + 16 , Tau(10+16 intron mutation)Tg, line 609 B6C3F1 embryos, backcrossed to C57BL/6 MAPT MAPT IVS10+16 C>T This model expresses a tau minigene driven by the mouse CAMKIIα promoter. The minigene encodes human tau 441, including partial intronic sequences flanking exon 10 of MAPT. The intronic mutation, IVS10 +16 C>T, was introduced by site-directed mutagenesis. MAPT: Transgenic Frontotemporal Dementia, Alzheimer's Disease, Other Tauopathy Aggregated tau in neurons of the entorhinal cortex, hippocampus, and cerebral cortex at advanced ages. Intraneuronal accumulation of tau oligomers in the hippocampus. Neuronal loss in the entorhinal cortex and hippocampus. Gliosis. Some hippocampal areas affected by age-related synaptic dysfunction and reduced synaptic density. Impaired spatial reference memory as measured by the Morris water maze by 6 months of age.  Human tau transcripts containing exon 10 are over-represented in the adult mouse brain, leading to elevated levels of 4R tau relative to 3R tau. Available through Hiroshi Mori and Takami Tomiyama Umeda et al., 2013 Yes
Transgenic caspase-cleaved tau BALB/C MAPT These transgenic mice express a truncated form of human tau (0N4R) that lacks the last 20 acids of the C-terminus, thus recapitulating the tau fragment produced by caspase cleavage (TauC3). Expression in the brain is driven by the promoter of the angiogenesis inhibitor 1 associated protein 4 (BAI1-AP4) gene. MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia No significant cell loss or astrogliosis in the brain. Age-dependent reduction in synaptic proteins (e.g. synaptophysin, PSD95) by 1.3 to 3 months of age. Hyperphosphorylated tau oligomers and aggregates. Learning and memory deficits by 1.3 to 3 months of age, as assessed by the Y-maze and passive avoidance tests. No significant motor impairment. Normal lifespan. Unknown Kim et al., 2016 Yes
mTau-E10-KO Mixed background (BALB/c x C57B1/B6 x B6D2F1) MAPT Gene-targeted deletion of exon 10 in murine tau gene. MAPT: Knock-Out Alzheimer's Disease, Frontotemporal Dementia No overt neuropathology at 12 months of age. Age-dependent deterioration of sensorimotor functions, including coordination deficits on the Rotarod and a decrease in muscle strength. No deficits in learning or memory. Humanized splicing pattern of murine tau, leading to the production of 3R tau rather than 4R tau. No anxiety phenotype. Mice are no longer available, but frozen ES cells are available through Lars Nilsson or Astrid Gumucio Gumucio et al., 2013 No
"Proaggregation mutant", TauΔK, hTau40Δ280 Unknown. MAPT MAPT K280del These are bigenic mice in which the TET-OFF system is used to temporally control human tau expression in the brain. Tetracycline transactivator (tTA) is downstream of the CAMKII-α promoter, driving expression in excitatory neurons in the forebrain. tTA in turn stimulates expression of the responder transgene, full-length human tau (hTau40, 2N4R) carrying the FTD-associated deletion, ΔK280. MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia Abundant pre-tangle pathology, but only rare mature tangles, and only at advanced ages. Tau pathology included mislocalization of tau to the somatodendritic compartment, aggregation, and hyperphosphorylation. Unknown. Unknown. Eckermann et al., 2007 Yes
Tau.P301L, hTau.P301L, Tau-4R-P301L, Tau(P301L) Thy1-hTau.P301L FVB/N MAPT MAPT P301L These transgenic mice overexpress the human Tau-4R/2N isoform bearing the P301L mutation under the control of the neuron-specific murine Thy1 promoter. MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia Pathologic hyperphosphorylation and conformational change of parenchymal tau in brain tissues starting at 7 months. Tangle-like pathology is mainly observed in the brain stem and spinal cord, and to a lesser extent in the midbrain and cerebral cortex. Age-dependent increase in total tau in CSF. Age-associated deficits in a passive avoidance task (starting at 5 months) and a novel object recognition task (starting at 9 months). At a young age (~2 months) outperforms wild-type littermates in object recognition memory. Progressive motor impairment and reduced activity, accompanied by increased clasping of hind and then forelimbs around seven months. Premature death around 8-12 months, preceded by weight loss, hyperkyphosis, reduced activity, and upper airway dysfunction. Available through reMYND Terwel et al., 2005 Yes
Line PS19, PS19Tg B6;C3-Tg(Prnp-MAPT*P301S)PS19Vle/J (C57BL/6 x C3H)F1 MAPT MAPT P301S Transgenic line expressing mutant human tau under the direction of the mouse prion protein (Prnp) promoter. The transgene codes for tau with four microtubule-binding domains and one N-terminal insert (4R/1N). MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia Neuron loss and brain atrophy by eight to 12 months, especially in the hippocampus and spreading to the neocortex and entorhinal cortex. Neurofibrillary tangles in the neocortex, amygdala, hippocampus, brain stem, and spinal cord. Neuroinflammation with microgliosis and astrocytosis. Impairments in spatial memory and learning ability in Morris water maze. Paralysis at seven to 10 months associated with a hunched-back posture followed by feeding difficulties. About 80 percent mortality by 12 months with median survival of about nine months. Clasping and limb retraction when lifted by the tail at three months, followed by limb weakness and brain atrophy. Homozygous females do not mate. The Jackson Lab: Stock# 008169; Live Yoshiyama et al., 2007 Yes
Triple transgenic, 3Tg B6.D2-Tg(Thy1-APPSwe, Prp-PSEN2N141I, Thy1-TauP301L) C57BL/6, DBA/2; backcrossed to C57BL/6 APP, MAPT, PSEN2 APP KM670/671NL (Swedish), MAPT P301L, PSEN2 N141I (Volga German) PS2APP mice (line B6.152H) x tau mice (line B6.TauP301L). PS2APP were generated by co-injecting two transgenic constructs: human PSEN2 (N141I mutation) and human APP (Swedish mutation) driven by the mouse prion promoter and the mouse Thy1 promoter respectively. The transgenic TauP301L mouse (line pR5) expresses the human tau40 isoform driven by the Thy1.2 promoter. APP: Transgenic; MAPT: Transgenic; PSEN2: Transgenic Alzheimer's Disease Phosphorylated tau accumulation in the subiculum and the CA1 region of the hippocampus at 4 months. Neurofibrillary tangles in these regions as well as the amygdala. Amyloid plaques. Dystrophic neurites and neuropil threads containing abnormally phosphorylated tau. No overt neuronal loss. Impaired spatial learning in the Morris water maze at 4 months but impairment is not progressive between 4 and 12 months and appears to be independent of pathology. Cortex-specific deficiencies in oxidative phosphorylation. Loss of mitochondrial membrane potential. Reduced cortical ATP. Increased superoxide anions and ROS compared to wild-type. No differences in APP expression, APP cleavage or Aβ accumulation compared to PS2APP. Levels of ptau422 increased in an age-dependent manner, but levels of ptau231 did not. Available through Laurence Ozmen Grueninger et al., 2010 Yes
TgTauR406W, Tau R406W-CAMKII B6SJL/F1; backcrossed to C57BL/6J MAPT MAPT R406W Human 4-repeat tau cDNA with the R406W mutation containing myc and FLAG tags at N-and C-terminal ends, respectively, and driven by the CaMK-II promoter. MAPT: Transgenic Frontotemporal Dementia, Alzheimer's Disease Argyrophilic and congophilic tau inclusions in neurons of the forebrain with age. Detectable with Congo red, thioflavin-S and Gallyas silver stain. Congophilic tau inclusions also in the hippocampus and amygdala. Mainly straight tau filaments. Impairments in contextual and cued fear conditioning at 16–23 months compared with wild-type littermates. No detectable sensorimotor deficits. No differences from wild-type in body weight, sensorimotor reflexes (acoustic startle response), or motor coordination (accelerating rotarod and pole tests).  Attenuation of the Schaffer collateral-evoked neural response in hippocampal slices. Decrease in prepulse inhibition. Higher mortality. Unknown Tatebayashi et al., 2002 Yes
“Proaggregation mutant”, TauRDΔ, TauRD, TauRD/ΔK280, TauRDΔK C57BL/6 MAPT MAPT K280del Regulatable expression of an abbreviated human tau sequence (amino acids 244-372) encompassing the four microtubule-binding repeat domains and carrying the ΔK280 mutation. Transgene is driven by the forebrain-specific CAMKIIα promoter. TET-OFF system in which the transgene is regulated by the tetracycline transactivator (tTA) and turned off by administration of doxycycline. MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia Tau aggregates and tangles as early as 2-3 months after gene expression. Gallyas silver-positive neurons abundant in the entorhinal cortex and amygdala, spreading to the neocortex by 15 months. “Ballooned” neurons. Astrogliosis. Synaptic structural changes and reduced synaptic number. Hippocampal neuronal loss. Reversible learning and memory deficits in the Morris water maze and passive avoidance test. No significant motor deficit, although slight reduction in Rotarod performance. Missorting of tau into the somato-dendritic compartment. Calcium dysregulation at synaptic boutons. Deficits in synaptic plasticity, including LTP and LTD. Unknown Mocanu et al., 2008 Yes
MAPT V337M, Tg214 B6SJL/F1 MAPT MAPT V337M (Seattle Family A) Human 4-repeat tau driven by the PDGF-β promoter. Tagged with myc and Flag on the N- and C-terminals respectively. MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia SDS-insoluble tau aggregates in hippocampus. Degenerating neurons in the hippocampus containing phosphorylated and ubiquitinated tau aggregates with β-sheet structure. Higher overall spontaneous locomotion than non-transgenic littermates in elevated plus maze. No differences in the Morris water maze. The amount of mutant tau varied, but was generally less than one tenth of endogenous tau levels. In hippocampal slices there was attenuation of the Schaffer collateral-evoked neural response. Unknown Tanemura et al., 2002, Tanemura et al., 2001 Yes
Truncated beta-amyloid 42 C57BL6 APP Transgenic vector expresses a human N-terminally truncated Aβ sequence (3-42) fused to thyrotropin-releasing hormone. The transgene is under the control of the murine Thy1.2 regulatory sequence. The glutamate at position 3 of Aβ was mutated to glutamine to facilitate pyroglutamate formation by the enzyme glutaminyl cyclase. APP: Transgenic Alzheimer's Disease Intraneuronal accumulation of Aβ peptides in the hippocampus by 3 months and in cerebellar nuclei by 6 months. Marked gliosis in the hippocampus by 12 months. Very rare extracellular Aβ deposits. Age-dependent behavioral deficits, including working memory as assessed by the cross maze at 12 months, but not at 3 or 6 months. Early and persistent decrease in anxiety in the elevated plus maze. Comparable to wild-type in general motor coordination at 3 and 6 months as indicated by the balance-beam test, but impairment at 12 months. Available through Thomas Bayer Wittnam et al., 2012 Yes
Transgene injected into C3H x C57Bl/6 embryos and then crossed with C57Bl/6. TARDBP TARDBP A315T Full-length human TDP-43 with the A315T mutation introduced by site-directed mutagenesis. The transgene is driven by the endogenous human promoter. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Cytoplasmic inclusions of TDP-43, axonal changes, gliosis, no overt neuronal loss or loss of axons. Increased levels of cytotoxic 25 kDA C-terminal fragment of TDP-43. Age-associated cognitive and motor deficits as measured by the passive avoidance test and the Rotarod. Normal lifespan and fertility. Available through Jean-Pierre Julien Swarup et al., 2011 Yes
line 23 STOCK Tg(Prnp-TARDBP*A315T)23Jlel/J Transgene injected into fertilized hybrid B6SJLF1oocytes. Founders bred with CD1 to create hybrid CD1 and B6SJLF. TARDBP TARDBP A315T Transgene encodes full-length human TDP-43 with the A315T mutation. The mouse prion protein (Prp) promoter drives transgene expression. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia No overt neuronal loss in the brain or spinal cord. Ubiquitin-positive cytoplasmic inclusions in neurons of the ventral horn and brainstem. Astrocytosis. Cytoplasmic aggregates of TDP-43 are largely absent, although some phospho-TDP-43 inclusions at end-stage. Progressive motor impairment characterized by weakness, a decline in grip strength, and reduction in stride length. Weakness was usually more pronounced in the hindlimbs. Prior to motor deficits, mice exhibit increased fat storage, decreased lean muscle mass, and larger adipocytes in white fat. The Jackson Lab: Stock# 016143; Cryopreserved Stallings et al., 2010 Yes
Transgene injected into C3H x C57Bl/6 embryos. Founders backcrossed with C57Bl/6. TARDBP TARDBP G348C Full-length human TDP-43 with the G348C mutation introduced by site-directed mutagenesis. The transgene is driven by the endogenous human TARDBP promoter. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Cytoplasmic inclusions of TDP-43 in neurons, axonal changes, denervated NMJs, gliosis, no overt neuronal loss or loss of axons. Increased levels of cytotoxic 25 kDA C-terminal fragment of TDP-43. Age-associated cognitive and motor deficits as measured by the passive-avoidance test, the Barnes maze, and the Rotarod. Impaired recovery after crush injury to the sciatic nerve (e.g., delayed recovery of motility and reduced axon regrowth). Normal lifespan and fertility. Available through Jean-Pierre Julien Swarup et al., 2011 Yes
TDP-43 M337V PrP (line 4) C57BL/6-Tg(Prnp-TARDBP*M337V)4Ptrc/J Transgene injected into fertilized C57BL/6 oocytes. Founders bred with B6. TARDBP TARDBP M337V Transgene expresses full-length human TARDBP with the M337V mutation, driven by the mouse prion protein (PrP) promoter. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia No overt neuronal death. Microgliosis and astrogliosis. Abnormal mitochondria in the form of eosinophilic aggregates in spinal motor neurons. Widespread ubiquitination and accumulation of phospho-tau. Body tremors and gait difficulties before one month of age, leading to a “dragging” gait. An inability to right themselves precipitating euthanasia around one to two months of age. Reduced brain and body weight compared with non-Tg littermates. The Jackson Lab: Stock# 017604; Cryopreserved Xu et al., 2011 Yes
Mt-TAR6/6 Transgene injected into BL6/SJL oocytes. Founders crossed to C57BL6/J. TARDBP TARDBP M337V The Thy-1.2 promoter drives expression of a transgene encoding human TARDBP with the M337V mutation. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Neuronal loss in cortical layer V motor neurons, spinal anterior horn motor neurons, CA regions of the hippocampus, and thalamic neurons. Astrogliosis and microgliosis. Diffuse cytoplasmic ubiquitin in cortical and spinal motor neurons and hippocampus, but rare overt inclusions. Deformed mitochondria and fission deficits. Progressive motor impairment, involving a hunched posture, muscle twitches, and reduced mobility. Impaired Rotarod performance. Complete paralysis and premature death. Postnatal growth retardation and weight loss. Transgene induced downregulation in endogenous TDP-43. Increased caspase-3 expression. Ultrastructural mitochondria abnormalities. Unknown Janssens et al., 2013 Yes
Wild-type TDP-43 transgenic (line 3C), TDP-43PrP C57BL/6-Tg(Prnp-TARDBP)3cPtrc/J Transgene injected into fertilized C57BL/6 oocytes. Founders bred with B6. TARDBP Transgene expresses wild-type human TARDBP driven by the mouse prion protein (Prp) promoter. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia No overt neuronal death, but degenerating neurites and axons, gliosis, and vacuolization of myelin. Abnormal aggregates of mitochondria present as eosinophilic aggregates in spinal motor neurons. Dendritic spine loss in the hippocampus. Homozygous mice develop body tremors and gait impairments leading to a “swimming gait” and severe motor deficits requiring euthanasia. Early reductions in body and brain weight in homozygous mice. Reduced dendritic spines in the hippocampus and lower mRNA levels of synaptic markers. The Jackson Lab: Stock# 016608; Cryopreserved Xu et al., 2010 Yes
Transgene introduced into C57Bl6/C3H oocytes. Founders crossed to C57/Bl6 for a minimum of four generations. TARDBP TARDBP Q331K Full-length human TDP-43 with the Q331K mutation driven by the mouse prion protein (Prp) promoter. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Age-dependent lower motor loss, gliosis, NMJ abnormalities and loss. No TDP-43 aggregates or cytoplasmic mislocalization. A variety of motor impairments starting around 3 months of age including tremor, abnormal hindlimb clasping, decreased Rotarod performance, and a later decrease in grip strength. Unknown Arnold et al., 2013 Yes
Elliott model, WT TDP-43 (line 4) Transgene injected into B6SJLF1 oocytes. Founders crossed with CD1 mice. TARDBP Transgene expressing full-length, wild-type, human TDP-43 driven by the mouse prion protein (Prp) promoter. Transgene integrated on X chromosome. TARDBP: Transgenic Amyotrophic Lateral Sclerosis No overt neuronal loss in the brain or spinal cord.   Progressive motor impairment (variable penetrance) starting with external rotation of one hind limb followed by bilateral weakness and low muscle tone. Relatively high TDP-43 expression in skeletal muscle. Myopathy, including variable muscle fiber size and disorganization of the muscle architecture. Ubiquitin-positive inclusions in skeletal muscle cells. Status of original hybrid unknown. This model is available on a B6SJL background through The Jackson Lab: Stock# 016201; Cryopreserved Stallings et al., 2010 Yes
Julien model, Wild-type TDP-43 Transgene injected into C3H x C57Bl/6 embryos. Founders crossed with C57Bl/6. TARDBP Full-length, wild-type, human TDP-43 driven by the endogenous human promoter. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Some denervated NMJs, gliosis (microgliosis and astrogliosis), no overt neuronal loss or loss of axons. Mostly nuclear expression of TDP-43. Age-associated cognitive and motor deficits as measured by the passive avoidance test, Barnes maze, and Rotarod. Impaired recovery following crush injury to the sciatic nerve (e.g., delayed recovery of motility, reduced axon regrowth). Normal lifespan and fertility. Not available: extinct Swarup et al., 2011 Yes
WT-TAR4/4, WT-TAR4 B6;SJL-Tg(Thy1-TARDBP)4Singh/J Transgene introduced into BL6/SJL oocytes. Founders crossed to C57BL6/J. TARDBP Transgene encodes wild-type human TARDBP, driven by the murine Thy-1 promoter. The transgene integrated at locus 6qB3 in the mouse genome and does not interrupt any known gene. TARDBP: Transgenic Amyotrophic Lateral Sclerosis, Frontotemporal Dementia Neuronal loss in the brain and spinal cord, including anterior cortex, CA3 hippocampus, Purkinje cells, and spinal cord. Astrogliosis and microgliosis especially in the anterior cortex. Widespread diffuse ubiquitin in neurons of the brain and spinal cord, including cytoplasmic and nuclear inclusions, some co-labeling for TDP-43. Progressive motor impairment, starting at postnatal day 14, with an abnormal hindlimb reflex. Gait abnormalities, including reduced stride length and impaired performance on the accelerating Rotarod. Quick progression to muscle fasciculation’s and spasms, followed by paralysis and premature death. Elevated anxiety at a young age. Size and weight of homozygotes lag behind non-Tg and hemizygous littermates. The Jackson Lab: Stock# 012836; Cryopreserved Wils et al., 2010 Yes
line 102 B6.Cg-Tg(tetO-APPSwInd)102Dbo/Mmjax C57BL/6 x C3HeJ; backcrossed to C57BL/6 APP APP KM670/671NL (Swedish), APP V717F (Indiana) Mouse APP695 with a humanized Aβ region and the Swedish (KM570/571NL) and Indiana (V617F) mutations downstream of a tetracycline-responsive promoter and mouse prion protein exons 1-2. APP: Transgenic Alzheimer's Disease APP protein 10-30x higher than endogenous mouse APP. Progressive amyloid plaques starting at 2 months. Extensive amyloid pathology by 9 months especially in the cortex and hippocampus. Amyloid pathology is halted by transgene suppression but existing plaques are stable. Highest doxycycline sensitivity relative to lines 107 and 885. Hyperactivity. The Jackson Lab; available through the JAX MMRRC Stock# 034845; Cryopreserved Jankowsky et al., 2005 No
line 107 B6.Cg-Tg(tetO-APPSwInd)107Dbo/Mmjax C57BL/6 x C3HeJ; backcrossed to C57BL/6 APP APP KM670/671NL (Swedish), APP V717F (Indiana) Mouse APP695 with a humanized Aβ region and the Swedish (KM570/571NL) and Indiana (V617F) mutations downstream of a tetracycline-responsive promoter and mouse prion protein exons 1-2. APP: Transgenic Alzheimer's Disease APP protein 10-30x higher than endogenous mouse APP. Progressive amyloid plaques starting at 2 months. Extensive amyloid pathology by 9 months especially in the cortex and hippocampus. Amyloid pathology is halted by transgene suppression but existing plaques are stable. Intermediate expression of transgene and doxycycline sensitivity relative to lines 102 and 885. Hyperactivity. The Jackson Lab; available through the JAX MMRRC Stock# 034846; Cryopreserved Jankowsky et al., 2005 No
line 885 B6C3-Tg(tetO-APPSwInd)885Dbo/Mmjax C57BL/6 x C3HeJ; backcrossed to C57BL/6 APP APP KM670/671NL (Swedish), APP V717F (Indiana) Mouse APP695 with a humanized Aβ region and the Swedish (KM570/571NL) and Indiana (V617F) mutations downstream of a tetracycline-responsive promoter and mouse prion protein exons 1-2. APP: Transgenic Alzheimer's Disease APP protein 10-30x higher than endogenous mouse APP. Progressive amyloid plaques starting at 2 months. Extensive amyloid pathology by 9 months especially in the cortex and hippocampus. Amyloid pathology is halted by transgene suppression but existing plaques are stable. Highest transgene expression and highest doxycycline requirement relative to lines 102 and 107. Hyperactivity. The Jackson Lab; available through the JAX MMRRC Stock# 034834; Cryopreserved Jankowsky et al., 2005 No
Hsiao mice, App-Swe, App-sw, APP(sw) B6;SJL-Tg(APPSWE)2576Kha B6;SJL Mixed Background APP APP KM670/671NL (Swedish) The human APP gene (isoform 695) containing the double mutation K670N, M671L (Swedish mutation) under the control of the hamster prion protein. APP: Transgenic Alzheimer's Disease Numerous parenchymal Aβ plaques by 11-13 months with some vascular amyloid. Oxidative lipid damage, astrogliosis and microgliosis. No tangles or neuronal loss. Impaired spatial learning, working memory, and contextual fear conditioning reported at <6 months although other studies have reported normal cognition at this age with progressive impairment by >12 months. Between 7 -12 weeks males become aggressive and begin to fight. Premature mortality: mortality of >20% anticipated, particularly in males. Taconic: Stock #1349 and Charles River.  Also available at the CRO PsychoGenics Hsiao et al., 1996 Yes
APPSwe-Tau, APPSwe(2576)/TauJNPL3, TAPP Tg(APPSWE)2576Kha Tg(Prnp-MAPT*P301L)JNPL3Hlmc C57BL/6, DBA/2, SJL, SW Mixed Background APP, MAPT APP KM670/671NL (Swedish), MAPT P301L Generated by crossing Tg2576 mice, which have the transgene for human APP (isoform 695) carrying the Swedish mutation with mice expressing human MAPT (4 repeat) with the P301L mutation. APP; MAPT: Transgenic Alzheimer's Disease Gradual appearance of plaques; by 9 months plaques are scattered throughout the cortex, hippocampus, and amygdala similar to Tg2576. Tau pathology more extensive than JNPL3. Astrocytosis and microgliosis. Motor disturbances similar to JNPL3, with identical range in age of onset. Reduced vocalization and decreased grooming. Progressive hindlimb weakness. Hunched posture. Eye irritations. Some mice have the Pde6brd1 retinal degeneration mutation which can cause light sensitivity and/or blindness and may affect behavioral testing. Taconic: Stock# 2469 Lewis et al., 2001 Yes
Tg-Aβ(4-42) C57BL6 APP Transgenic encodes N-truncated human Aβ (Aβ4-42) fused to the murine thyrotropin releasing hormone signal peptide under the control of the Thy1 promoter. APP: Transgenic Alzheimer's Disease Aβ4-42 is dectable starting at two months, predominantly in the CA1 region of the hippocampus, but also in the occipital cortex, piriform cortex, striatum, and superior colliculus. Age- and dose-dependent hippocampal neuronal loss is seen in the CA1 region as well as microgliosis and astrogliosis. Age-dependent spatial learning deficit as demonstrated in the Morris water maze, specifically, the absence of a preference for the target quadrant starting at eight months in homozygous mice and at 12 months in hemizygous mice. Impaired contextual fear conditioning. Intact vision and motor abilities. Available through Thomas Bayer Bouter et al., 2013 Yes
B6CBA-Tg(Thy1.2-hAPParc) C57BL/6-CBA APP APP E693G (Arctic) Transgenic mice with human APP (isoform 695) bearing the Arctic APP mutation (E693G). APP: Transgenic Alzheimer's Disease Mild amyloid pathology with a relatively late onset, starting with intracellular Aβ, then diffuse extracellular Aβ deposits in the subiculum, expanding to interconnected brain regions such as retrosplenial granular cortex, thalamus, and mammillary bodies. Pathology more severe in females. Spatial learning and memory deficit in the Barnes maze test in heterozygous females mice at 15 months. Available through Annica Rönnbäck Rönnbäck et al., 2011 No
R1 line of ES cells APP APP KM670/671NL (Swedish) Modification of mouse APP sequence to introduce the Swedish mutation and "humanize" the murine Aβ sequence by altering three amino acids. APP: Knock-In Alzheimer's Disease Accumulation of human Aβ. Unknown. Unknown Reaume et al., 1996 No
tg ArcSwe, APP-ArcSwe C57BL/6J APP APP KM670/671NL (Swedish), APP E693G (Arctic) Transgene with human APP (isoform 695) containing both the Arctic (E693G) and Swedish (KM670/671NL) mutations under the murine Thy1 promoter. APP: Transgenic Alzheimer's Disease, Cerebral Amyloid Angiopathy Strong intraneuronal Aβ aggregation starting at 1 month and increasing with age. Extracellular amyloid plaque at 5-6 months, most consistent in the cerebral cortex, hippocampus, and thalamus. Congophilic parenchymal plaques are predominant, but some mice show marked CAA, particularly in the thalamus. Mild spatial learning deficits at 4-8 months in Morris water maze and impaired functioning in a passive avoidance test at 16 months. Tg-ArcSwe have reduced body weight compared with nontransgenic littermates. Available through Lars Nilsson Lord et al., 2006 Yes
APP(swe/ind) CRND8 Hybrid C3H/He-C57BL/6 APP APP KM670/671NL (Swedish), APP V717F (Indiana) Transgene contains human APP695 with the Swedish mutation (KM670/671/NL) and Indiana mutation (V717F) under the control of the hamster prion (PrP) gene promoter. The expression cassette includes about 90 nucleotides of the APP 5'-untranslated region adjacent to the start codon and 269 nucleotides of the 3′-untranslated region. APP: Transgenic Alzheimer's Disease Rapid, early plaque development, with thioflavin S-positive amyloid deposits at 3 months; dense cored plaques and neuritic pathology by 5 months. Plaques become more extensive with age. More Aβ42 than Aβ40. Activated microglia appear concurrently with plaques, whereas GFAP+ astrocytes follow later, about 13-14 weeks. Dystrophic neurites at 5 months . Early impairment in acquisition and learning reversal in the reference memory version of the Morris water maze by 3 months. Cognitive deficits in the step-down inhibitory avoidance test at 7 months but not at 2 months. Similar to wild-type in motility, exploratory activity, or neuromuscular function at 7 months as evaluated by the rotarod, hole board and grip strength tests. Cholinergic dysfunction: decrease in the number of cholinergic neurons in the nucleus basalis magnocellularis by 7 months as measured by ChAT immunoreactivity. Enhanced auditory startle response and modest reduction in prepulse inhibition. Available through the Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto Chishti et al., 2001 Yes
BRI2(Tg-FDD) Hybrid C3HeB/FeJ embryo; crossed to C57BL/6J ITM2B (BRI2) BRI2: Familial Danish Dementia (FDD) duplication The transgene, driven by the mouse prion promoter (Prnp), consists of the 795 form of human BRI(2) with a 10-nucleotide duplication-insertion (TTTAATTTGT). ITM2B (BRI2): Transgenic Familial Danish Dementia, Cerebral Amyloid Angiopathy, Alzheimer's Disease Widespread cerebral amyloid angiopathy (CAA) starting around 7 months. Deposition of the Danish amyloid subunit (ADan) in brain parenchyma and vessels, along with amyloid-associated gliosis and inflammation, intracellular and extracellular deposition of oligomeric ADan, and tau-positive deposits in neuropil, but no neurofibrillary tangles. Age-dependent abnormal grooming behavior. Around one year mice develop an arched back and walk with a wide-based gait and short steps. Feet clasping upon suspension of the mice by their tails. Available through Ruben Vidal Vidal et al., 2009 No
mAPP/DN-RAGE, APP/DN-RAGE C57BL/6 APP, RAGE (AGER) APP KM670/671NL (Swedish), APP V717F (Indiana) Mice expressing a form of transgenic RAGE comprising a truncated form of the receptor with intact extracellular and membrane-spanning portions, but a deleted cytosolic tail driven by the PDGF-β promoter were crossed with mice expressing human APP carrying the Swedish and Indiana mutations driven by PDGF-β promoter (The Jackson Lab: Stock# 004661--now extinct). APP: Transgenic; RAGE (AGER): Transgenic Alzheimer's Disease Diminished neuropathology compared with mice expressing mutant APP alone at both 3–4 and 14–18 months of age. Preservation of spatial learning and memory compared with Tg-mAPP/RAGE animals. No abnormalities with respect to reproductive fitness, development, basic neurological functioning, or longevity. Available through Shirley ShiDu Yan Arancio et al., 2004 No
APP/RAGE C57BL/6 APP, RAGE (AGER) APP KM670/671NL (Swedish), APP V717F (Indiana) Mice expressing human wild-type RAGE driven by the PDGF-β promoter were crossed with mice expressing human APP carrying the Swedish and Indiana mutations driven by PDGF-β promoter (The Jackson Lab: Stock# 004661-now extinct) APP: Transgenic; RAGE (AGER): Transgenic Alzheimer's Disease Increased activation of microglia and astrocytes compared to mice expressing mutant APP alone. Abnormalities in spatial learning and memory at 3-4 months of age, whereas deficits occur later in mice expressing mutant APP alone and are less severe. Available through Shirley ShiDu Yan Arancio et al., 2004 No
APP-Swedish,Dutch,Iowa, APPSwDI C57BL/6-Tg(Thy1-APPSwDutIowa)BWevn/Mmjax C57BL/6 APP APP KM670/671NL (Swedish), APP E693Q (Dutch), APP D694N (Iowa) Transgenic mice with 2.1 kb of the human APP gene (isoform 770) with the Swedish (K670N/M671L), Dutch (E693Q) and Iowa (D694N) mutations under the control of the mouse Thy1 promoter. APP: Transgenic Alzheimer's Disease, Cerebral Amyloid Angiopathy, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch type Hemizygotes progressively accumulate insoluble Aβ40 and Aβ42, especially within brain microvessels starting at 3 months. Fibrillar Aβ in micovessels around 6 months. Diffuse plaque-like deposits around 3 months in the subiculum, hippocampus and cortex. Aβ deposits throughout the forebrain by 12 months. Impaired learning and memory in the Barnes maze task at 3, 9, and 12 months. Beginning at 3 months transgenic mice took longer to find the escape hole. No difference in mobility, strength or coordination. The Jackson Lab; available through the JAX MMRRC Stock# 034843; Live Davis et al., 2004 Yes
tg-APPSwe C57BL/6J APP APP KM670/671NL (Swedish) Transgene with human APP (isoform 695) bearing the Swedish mutation under the murine Thy1 promoter. APP: Transgenic Alzheimer's Disease Extracellular amyloid deposition begins at ~12 months. Intraneuronal Aβ aggregates at ~6 months. Extracellular pathology, both cerebrovascular amyloid angiopathy (CAA) and congophilic parenchymal plaques, mainly found in the cerebral cortex, hippocampus and thalamus. Aβ-burden in cerebral cortex is approximately 1.0% (at 12 months) and 2.8% (at 18 months). Unknown. Available through Lars Nilsson Philipson et al., 2009, Lord et al., 2006 Yes
Tau22 C57BL6/CBA; backcrossed to C57BL6 MAPT MAPT G272V, MAPT P301S Transgene containing the cDNA of the 412 amino acid isoform of human 4-repeat tau mutated at sites G272V and P301S under a Thy1.2 promotor. MAPT: Transgenic Frontotemporal Dementia, Alzheimer's Disease A variety of tau pathologies starting at 3 months, including neurofibrillary tangle-like inclusions, rare ghost tangles, and paired helical filament-like structures. Hyperphosphorylation of tau on many epitopes (e.g. AT8, AT100, AT180, AT270, 12E8, tau-pSer396, and AP422) and mild astrogliosis. Increased anxiety and delayed learning from 3 months, and reduced spatial memory at 10 months. No changes in overall motor activity and no gross motor deficits. Increased depression-like and aggressive behavior, co-occurring with disturbances in nocturnal activity. Fertile with normal frequency and size of litters. Stably transmits the transgene to offspring. Deficits in hippocampal synaptic transmission. Available through Luc Buée Schindowski et al., 2006 Yes
Thy-1 mutated human tau, TAU 441, hTAU441, TAU441 V337M R406W C57Bl/6xDBA MAPT MAPT V337M (Seattle Family A), MAPT R406W Transgene consists of human MAPT Tau441 (2N/4R) with mutations V337M and R406W under control of the Thy1 promoter. MAPT: Transgenic Alzheimer's Disease Increased total tau, and phosphorylated tau (Thr181, Ser199, Thr231) in amygdala and hippocampus starting at 3 months. Spatial memory deficits starting at 5 months (Morris water maze). Olfactory deficits at 5 months (Buried food test). No motor deficits (rota rod, beam walk) or depressive behavior (forced swim test). Olfactory deficits. QPS-Austria Flunkert et al., 2013 Yes
Thy-1 PS1.M146V Transgene injected into fertilized oocytes from pure C57BL/6 mice. PSEN1 PSEN1 M146V Transgene encoding human PSEN1 carrying the M146V mutation. Transgene is driven by the murine Thy-1 promoter. PSEN1: Transgenic Alzheimer's Disease No plaques. Unknown. Unknown Howlett et al., 2004 No
Segmentally trisomic Ts(1716)65Dn, Down Syndrome-segmental trisomy 16 B6EiC3Sn a/A-Ts(1716)65Dn/J DBA/2J Cesium irradiation produced a reciprocal translocation of chromosomes 16 and 17, creating a freely segregating, supernumerary chromosome Mmu1716 (1716). Other Alzheimer's Disease, Down's Syndrome Brain is grossly normal. Age-dependent cholinergic neurodegeneration and reduced NGF in the basal forebrain. Age-related elevation of APP and Aβ in the hippocampus but no β-amyloid pathology. Early developmental delay. Deficits in behavioral and cognitive tasks including spatial learning and memory deficits as assessed by the Morris water maze and the radial arm maze. Developmental delay in sensorimotor milestones. Locomotor hyperactivity. Lack of behavioral inhibition. Stereotypic behavior. Females are smaller, and produce fewer, smaller litters. Males are effectively sterile with hypospermia. The Jackson Lab: Stock# 001924; Live. Also available at the CRO PsychoGenics Davisson et al., 1990 No
Rat Models (6)
DJ-1 knockout rat LEH-Park7tm1sage Long Evans Hooded PARK7 (DJ1) Disruption of the DJ-1 gene by zinc finger nuclease (ZFN) technology. ZFNs were engineered to bind to a recognition sequence in exon 5 of PARK7 and cleave DNA. PARK7 (DJ1): Knock-Out Parkinson's Disease Age-related decrease in dopaminergic neurons in the substantia nigra; more than 50 percent reduction at eight months. Striatal dopamine and serotonin levels elevated 2-3fold over wild-type levels. Abnormalities in gait and strength. First deficits measured at 4 months of age; abnormal paw positioning and a shorter stride. Weak hind limbs with some dragging. Coordination largely intact. No increase in mortality up to 8 months of age. Available through Horizon Discovery (formerly Sage Labs). Cat #TGRL4830; Live. Dave et al., 2014 Yes
Line 10681, hBAC G2019S-LRRK2, LRRK2 G2019S rat NTac:SD-Tg(LRRK2*G2019S)571CJLi Sprague-Dawley LRRK2 LRRK2 G2019S BAC construct carrying the human gene Lrrk2 with the G2019S mutation. LRRK2: Transgenic Parkinson's Disease No overt neurodegeneration out to 12 months of age. Elongated dopaminergic neurons. Elevated oxidative and nitrosative stress. No evidence of gliosis. No α-synuclein inclusions until challenged with exogenous α-synuclein. No change in dopamine levels. Mild abnormalities in motor behavior. Slightly more postural instability at eight months of age (but not at four and 12 months). Slightly more rearing events at 12 months, but not at younger ages. Available through Taconic, Cat# 10681, Live. West et al., 2014 Yes
Lrrk2 knockout rat LEH-Lrrk2tm1sage Long Evans Hooded LRRK2 Zinc finger nuclease (ZFN) technology was used to generate a deletion of 10 base pairs in exon 30 of the rat Lrrk2 gene. This resulted in a frameshift and a premature stop codon in the same exon. LRRK2: Knock-Out Parkinson's Disease Not observed. Protection against dopaminergic cell loss under conditions involving LPS or α-synuclein overexpression in the substantia nigra. No data. Abnormalities in peripheral organs, including the kidney, liver, and lung. Available through Horizon (formerly Sage Labs), Cat #TGRL4620, Live. Baptista et al., 2013, Ness et al., 2013 Yes
Park2 KO, Parkin knockout rat LEH-Park2TM1sage Long Evans Hooded PRKN (parkin) The rat Park2 gene was disrupted using zinc finger nuclease (ZFN) technology. The targeted ZFN created a DNA strand break in exon 4 of Park2. Repair of this break created a deletion of five base pairs, leading to a frame shift and the creation of a premature stop codon. PRKN (parkin): Knock-Out Parkinson's Disease Minimal pathology. A non-significant reduction in dopaminergic neurons in the substantia nigra. No differences in striatal dopamine levels. Parkin KO rats exhibit normal behavior. Available through Horizon Discovery (formerly Sage Labs); TGRL4760; Live. Dave et al., 2014 Yes
Pink1 knockout rat, PARK6 KO rat LEH-Pink1tm1Sage-/- Long Evans Hooded PINK1 The rat Pink1 gene was disrupted using zinc finger nuclease (ZFN) technology. The ZFNs were engineered to bind to a recognition site in exon 4 of Pink1 and cleave the DNA. When the resulting double strand break was repaired, a deletion of 26 base pairs was created. This deletion lead to a frameshift and the creation of a premature stop codon. PINK1: Knock-Out Parkinson's Disease Age-related decrease in dopaminergic neurons in the substantia nigra; greater than 50 percent reduction at eight months. Striatal dopamine and serotonin levels elevated 2-3-fold over wild-type levels. Abnormalities in gait, coordination, and strength. First deficits measured at 4 months of age; abnormal paw positioning and a shorter stride, paw slips on balance bean. Weak hind limbs with dragging. Heavier than wild-type rats at 4, 6, and 8 months of age. No increase in mortality. Available through Horizon Discovery (formerly Sage Labs), Cat# TGRL4690; Live. Dave et al., 2014 Yes
α-synuclein (E46K) rat, founder line 70, Human α-synuclein E46K rat, E46K aSyn Rat, Alpha-synuclein E46K Rat (BAC Tg) NTac:SD-Tg(SNCA*E46K)70CJLi Sprague-Dawley SNCA SNCA E46K A bacterial artificial chromosome (BAC) was used to introduce human α-synuclein with the E46K mutation. SNCA: Transgenic Parkinson's Disease No overt neuronal loss. Accumulation of mutant α-synuclein in the brain, in the form of diffuse staining and intracellular aggregates. Aggregates were largely restricted to dopaminergic neurons of the substantia nigra and ventral tegmental area. Elevated nitrotyrosine in dopaminergic neurons. No overt behavioral changes until challenged with low-dose rotenone, upon which the rats exhibit bradykinesia, postural instability, and rigidity. Viable and fertile. Available through Taconic Cat #10679; Cryopreserved. Cannon et al., 2013 Yes

125 Visualizations

AD-related Research Models

Phenotypes Examined

  • Neuronal Loss
  • Plaques
  • Tangles
  • Gliosis
  • Changes in LTP/LTD
  • Cognitive Impairment
  • Synaptic Loss

When visualized, these phenotypes will distributed over a 18 month timeline demarcated at the following intervals: 3mo, 6mo, 9mo, 1yr, 15mo, 18mo+.

3xTg

Observed
  1. X
    Plaques at 26

    Extracellular Aβ deposits by 6 months in the frontal cortex, predominantly layers 4 and 5 and progress with age (Oddo et al., 2003).

  2. X
    Tangles at 52

    By 12 months extensive tau immunoreactivity in CA1 neurons of the hippocampus, particularly pyramidal neurons, later in the cortex. No tau pathology at 6 months (Oddo et al., 2003).

  3. X
    Gliosis at 30

    Increased density of GFAP immunoreactive astrocytes and IBA-1 immunoreactive microglia compared with wild-type mice at 7 months (Caruso et al., 2013). Development of gliosis may occur earlier.

  4. X
    Changes in LTP/LTD at 26

    By 6 months decreased LTP compared with wild type controls. Impairment in basal synaptic transmission. No change at 1 month of age (Oddo et al., 2003).

  5. X
    Cognitive Impairment at 17

    Cognitive impairment manifests at 4 months as a deficit in long-term retention and correlates with the accumulation of intraneuronal Aβ in the hippocampus and amygdala, but plaques and tangles are not yet apparent (Billings et al., 2005).

Absent
No Data
  • Neuronal Loss at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN1, MAPT APP KM670/671NL (Swedish), MAPT P301L, PSEN1 M146V APP: Transgenic; PSEN1: Transgenic; MAPT: Transgenic Alzheimer's Disease

Age-related, progressive neuropathology including plaques and tangles. Extracellular Aβ deposits by 6 months in frontal cortex, more extensive by 12 months. No tau pathology at 6 months, but evident at 12 months. Synaptic dysfunction, including LTP deficits, prior to plaques and tangles.

Cognitive impairment by 4 months. Impairments first manifest as a retention/retrieval deficit and not as a learning deficit, and occur prior to plaques and tangles. Deficits in both spatial and contextual based paradigms. Clearance of intraneuronal Aβ by immunotherapy rescues the early cognitive deficits in a hippocampal-dependent task.

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5xFAD

Observed
  1. X
    Neuronal Loss at 39

    Neuron loss in cortical layer 5 and subiculum.

  2. X
    Plaques at 7

    Amyloid deposition begins at 1.5 months and reaches high levels especially in subiculum and deep cortical layers. Aβ42 also accumulates intraneuronally in an aggregated form within the soma and neurites starting at 1.5 months (Oakley et al., 2006).

  3. X
    Gliosis at 9

    Gliosis begins at 2 months (Oakley et al., 2006).

  4. X
    Synaptic Loss at 39

    Synaptic markers synaptophysin, syntaxin, and PSD-95 decrease with age and are significantly reduced by 9 and 12 months.

  5. X
    Changes in LTP/LTD at 26

    LTP is normal in young animals, but becomes impaired around 6 months (Kimura et al., 2009); specifically, in hippocampal slices from < 4-month-old mice, I/O curves of fEPSPs were not different from those of wild-type controls, but the I/O responses at Schaffer collateral-CA1 synapses at 6 months were impaired.

  6. X
    Cognitive Impairment at 17

    Impaired spatial memory in Y-maze test at 4-5 months. Impaired stress-related memory, specifically significantly lower levels of contextual freezing at 6 months. Impaired remote memory stabilization at < 4 months.

Absent
  • Tangles at

    Absent.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN1 APP KM670/671NL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Amyloid pathology starting at 2 months, including amyloid plaques. Accumulation of intraneuronal Aβ before amyloid deposition. Gliosis and synapse degeneration. Neuron loss in cortical layer 5 and subiculum. No neurofibrillary tangles.

Age-dependent memory deficits including spatial memory, stress-related memory, and memory stablization. Motor phenotype and reduced anxiety.

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ADanPP

Observed
  1. X
    Plaques at 9

    Vascular amyloid deposits and punctate parenchymal aggregates first occur in the hippocampus and increase with age, spreading throughout the brain, including the cortex, amygdala, thalamus, and brainstem in hemizygous mice.

  2. X
    Gliosis at 17

    Astrogliosis and microgliosis increase with age and increasing ADan-amyloid deposition.

  3. X
    Cognitive Impairment at 78

    The only ages tested were 6 months and 18-20 months. Mice 18-20 months of age exhibited both motor and spatial learning defects in the Morris water maze, and increased anxiety in the open field test. No impairments were observed in 6 month-old mice.

Absent
  • Neuronal Loss at

    Absent.

  • Tangles at

    Absent.

No Data
  • Synaptic Loss at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
ITM2B (BRI2) BRI2: Familial Danish Dementia (FDD) duplication ITM2B (BRI2): Transgenic Familial Danish Dementia, Alzheimer's Disease, Cerebral Amyloid Angiopathy

ADan deposition starts in the hippocampus and meningeal vessels at 2 months and increases with age. By 18 months, deposition is widespread. The majority of amyloid deposits are associated with the vasculature, where they destroy the integrity of the vessel wall and lead to microhemorrhages. Parenchymal amyloid plaques surrounded by microglia and dystrophic neurites are also present.

Impaired performance in Morris water maze, due to a combination of both motor deficits (i.e. reduced swim speed) and spatial learning deficits reported at 18-20 months. Open field test at 18-20 months also showed an anxiety-related phenotype.

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APP23

Observed
  1. X
    Neuronal Loss at 61

    Neuronal loss (14-28%) has been reported in the CA1 region of the hippocampus in 14-18 month old mice (Calhoun et al., 1998).     

  2. X
    Plaques at 26

    Congophillic, dense-core amyloid plaques first appear at 6 months, and increase in size and number with age. Amyloid plaques can occupy more than 25% of the neocortex and hippocampus in 24 month-old mice (Sturchler-Pierrat et al., 1997; Calhoun et al., 1998).   

  3. X
    Gliosis at 26

    Activated microglia in close proximity to dense amyloid plaques (Stalder et al., 1999). Upregulation of neuroinflammatory markers and activation of astrocytes and macrophages. Age-associated increase in components of the complement system, namely C1q and C3, at later ages (9 and 18 months, respectively) (Reichwald et al., 2009). 

  4. X
    Cognitive Impairment at 13

    Spatial memory defects in Morris Water maze at 3 months and progresses with age (Van dam et al., 2003; Kelly et al., 2003).

Absent
  • Tangles at

    Dystrophic neurites containing hyperphopshorylated tau surounds Aβ plaques, but no neurofibrillary tangles are observed (Sturchler-Pierrat et al., 1997).

  • Synaptic Loss at

    Neocortical synapses were examined in mice as old as 24 months of age; no evidence of alterations in the number of synapses or levels of synaptophysin were observed (Boncristiano et al., 2005).

  • Changes in LTP/LTD at

    LTP in the hippocampus and prefrontal cortex is normal at all ages studied: 3, 6, 9, 12, 18 and 24 months (Roder at al., 2003).

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP KM670/671NL (Swedish) APP: Transgenic Alzheimer's Disease, Cerebral Amyloid Angiopathy

Aβ deposits first observed at 6 months. Congophilic plaques increase in size and number with age and are surrounded by activated microglia, astrocytes, and dystrophic neurites containing hyperphosphorylated tau (although no neurofibrillary tangles). Neuronal loss in the CA1 region of the hippocampus. Mice also develop CAA, and microhemorrages occur at later ages.

Spatial memory defects in Morris Water maze at 3 months and progresses with age. Memory deficits in passive avoidance were observed in 25 month-old mice, but not at younger ages.

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APP23 x PS1-R278I

Observed
  1. X
    Plaques at 26

    By 6 months of age amyloid plaques accumulate in the cortex and hippocampus. A high percentage of plaques are thioflavin-S –positive cored plaques.

  2. X
    Gliosis at 39

    Astrocytosis in the vicinity of plaques in the hippocampus and cortex by 9 months.

  3. X
    Cognitive Impairment at 13

    Short-term memory deficits are apparent by 3 to 4 months as measured by the Y maze.

Absent
  • Tangles at

    Not observed.

No Data
  • Neuronal Loss at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN1 PSEN1 R278I APP: Transgenic; PSEN1: Knock-In Alzheimer's Disease

Amyloid deposition by 6 months of age in the cortex and hippocampus. Abundant reactive astrocytes in the vicinity of plaques. Elevated Aβ43 in the brain by 3 months. High density of cored plaques. Pyroglutamate Aβ (N3pE-Aβ) associated with amyloid plaques.

Short-term memory deficits apparent by 3-4 months as measured by the Y maze.

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APP751SL/PS1 KI

Observed
  1. X
    Neuronal Loss at 23

    Some cell loss detectable as early as 6 months in female mice. At 10 months extensive neuronal loss (>50%) is present in the CA1/2 hippocampal pyramidal cell layer. SNeuronal loss also occurs in the frontal cortex and cholinergic system (Casas et al., 2004; Christensen et al., 2008; Christensen et al., 2010).

  2. X
    Plaques at 11

    Aβ deposition at 2.5 months compared to 6 months in APPSL mice. At 6 months, numerous compact Aβ deposits in the cortex, hippocampus, and thalamus, whereas in age-matched APPSL mice only very few deposits restricted mainly to the subiculum and deeper cortical layers. At 10 months, deposits increased in distribution, density, and size in both models (Casas et al., 2004).

  3. X
    Gliosis at 11

    Astrogliosis occurs in parallel with Aβ deposition, starting around 2.5 months, and in proximity to Aβ-positive neurons (Wirths et al., 2010).

  4. X
    Synaptic Loss at 24

    At 6 months, levels of pre- and post-synaptic markers are reduced (Breyhan et al., 2009).

  5. X
    Changes in LTP/LTD at 28

    At 6 months there is a large reduction of long-term potentiation and disrupted paired pulse facilitation. No deficit at 4 months (Breyhan et al., 2009).

  6. X
    Cognitive Impairment at 27

    Age-dependent impairments in working memory as measured by the Y maze and T-maze continuous alternation task. No deficit at 2 months, but deficits at 6 and 12 months compared to PS1KI littermates (Wirths et al., 2008).

Absent
  • Tangles at

    Absent.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN1 APP KM670/671NL (Swedish), APP V717I (London), PSEN1 M233T, PSEN1 L235P APP: Transgenic; PSEN1: Knock-In Alzheimer's Disease

Acceleration of extracellular Aβ deposition compared to the single transgenics. Age-dependent neuronal loss in the hippocampus with extensive neuronal loss in the CA1/2 at 10 months with detection as early as 6 months in female mice. Intraneuronal Aβ and thioflavin-S-positive deposits before neuronal loss. Astrogliosis in proximity of Aβ-positive neurons.

Age-dependent impairments in working memory as measured by the Y maze and T-maze continuous alternation task. No deficit at 2 months, but deficits at 6 and 12 months compared to PS1KI littermates.

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APPDutch

Observed
  1. X
    Gliosis at 126

    Microgliosis develops after the onset of CAA pathology and is prominent in areas adjacent to amyloid-laden vessels. There is also widespread activation of astrocytes in neocortical regions affected by CAA. These changes have been reported at 29 months of age, although the actual onset of gliosis may occur earlier than has been examined.

Absent
  • Plaques at

    No plaques are observed, but CAA develops at 22-24 months.

  • Tangles at

    Absent.

No Data
  • Neuronal Loss at

    Unknown.

  • Synaptic Loss at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

  • Cognitive Impairment at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP E693Q (Dutch) APP: Transgenic Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch type, Cerebral Amyloid Angiopathy, Alzheimer's Disease

Increased Aβ40/42 ratio. Extensive vascular Aβ deposition starting at 22-24 months appearing first in leptomeningeal vessels followed by cortical vessels, leading to smooth muscle cell degeneration, hemorrhages, and neuroinflammation. Parenchymal amyloid plaques are not observed. 

Unknown.

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APP E693Δ-Tg (Osaka)

Observed
  1. X
    Neuronal Loss at 104

    Neuronal loss, as measured by NeuN staining, was observed in the CA3 region of the hippocampus at 24 months of age. Neuronal loss was not detected in the cerebral cortex at this time.

  2. X
    Gliosis at 52

    At 12 months of age, microgliosis is seen in transgenic mice, as measured by the presence of Iba-1 staining in the hippocampus and cortex. Astrocytosis, as measured by GFAP-reactivity, increased starting around 18 months of age in these regions.

  3. X
    Synaptic Loss at 34

    Starting around eight months of age, transgenic mice exhibit a decrease in synaptic density in the CA3 region of the hippocampus as measured by synaptophysin staining.

  4. X
    Changes in LTP/LTD at 35

    By eight months of age, transgenic mice exhibit reduced short term plasticity as measured by paired-pulse facilitation in addition to reduced LTP as elicited by high frequency stimulation to the perforant pathway.

  5. X
    Cognitive Impairment at 36

    By 8 months of age, transgenic mice exhibit memory impairment in the Morris water maze compared to mice expressing equivalent levels of wild-type human APP.

Absent
  • Plaques at

    Extracelluar amyloid plaques are not observed out to 24 months; however, Aβ accumulates within neurons of the hippocampus and cerebral cortex starting around eight months of age.

  • Tangles at

    Overt tangle pathology is not observed out to 24 months of age, but abnormal tau phosphorylation is observed starting around eight months of age.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP E693del (Osaka) APP: Transgenic Alzheimer's Disease

Age-dependent accumulation of Aβ oligomers within hippocampal and cortical neurons, but negligible deposits of extracellular amyloid. Abnormal tau phosphorylation, but no overt tangle pathology. Synaptic loss and gliosis in hippocampus and cerebral cortex. Late neuronal loss in the CA3 region of the hippocampus.

Memory impairment by eight months as measured by the Morris water maze. Specifically, reduced spatial reference memory in the Morris water maze compared to mice expressing comparable levels of wild-type human APP.

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APP NL-F

Observed
  1. X
    Plaques at 26

    Homozygotes develop amyloid plaques starting at 6 months in the cortex and hippocampus. Heterozygotes develop amyloidosis after 24 months. Plaques contained Aβ1-42 and pyroglutamate Aβ (Aβ3(pE)-42); Aβx-40 was a minor species.

  2. X
    Gliosis at 26

    Microglia and activated astrocytes accumulate with age, starting around 6 months of age, concurrent with plaque formation.

  3. X
    Synaptic Loss at 39

    Reduced synaptophysin and PSD95 immunoreactivities associated with Aβ plaques at 9-12 months.

  4. X
    Cognitive Impairment at 78

    Memory impairment in homozygous mice at 18 months as measured by the Y maze test. APPNL/NL mice (with Swedish mutation only) were unimpaired at this age. No significant deficit was seen in the Morris water maze at 18 months.

Absent
  • Neuronal Loss at

    Absent.

  • Tangles at

    Absent; although elevated levels of phosphorylated tau are observed in dystrophic neurites around plaques.

No Data
  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP KM670/671NL (Swedish), APP I716F (Iberian) APP: Knock-In Alzheimer's Disease

Elevated Aβ peptides accumulating into plaques starting at 6 months. Microgliosis and astrocytosis, especially around plaques. Reduced synaptophysin and PSD-95 indicative of synaptic loss. No tangle pathology or neurodegeneration.

Memory impairment by 18 months as measured by the Y maze. No significant impairment in the Morris water maze.

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APP NL-G-F

Observed
  1. X
    Plaques at 9

    Aggressive amyloidosis; plaques develop in homozygous mice starting at 2 months with near saturation by 7 months. Aβ deposition at 4 months in heterozygous mice. Cortical and subcortical amyloidosis present.

  2. X
    Gliosis at 9

    Microglia and activated astrocytes accumulate with age starting around 2 months, especially around plaques in a manner concurrent with plaque formation.

  3. X
    Synaptic Loss at 17

    Reduction of synaptophysin and PSD95 immunoreactivities associated with Aβ plaques in both cortical and hippocampal areas.

  4. X
    Cognitive Impairment at 26

    Memory impairment in homozygous mice by 6 months of age as measured by the Y maze.

Absent
  • Neuronal Loss at

    Absent.

  • Tangles at

    Absent; although phosphorylated tau is elevated in dystrophic neurites around plaques.

No Data
  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP KM670/671NL (Swedish), APP I716F (Iberian), APP E693G (Arctic) APP: Knock-In Alzheimer's Disease

Aggressive amyloidosis with deposition in the cortex beginning at 2 months and approaching saturation by 7 months. Aβ deposition in heterozygous mice at 4 months. Subcortical amyloidosis. Exacerbated microgliosis and astrocytosis compared to APPNL-F mice. Reduced synaptophysin and PSD-95 indicative of synaptic loss. No tangle pathology or neurodegeneration.

Memory impairment by 6 months as measured by the Y maze.

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APPPS1

Observed
  1. X
    Neuronal Loss at 74

    Global neuron loss is not observed, but modest neuron loss was found in the granule cell layer of the dentate gyrus and other subregions with high neuronal density in 17-month old animals (Rupp et al., 2011).

  2. X
    Plaques at 6

    Aβ deposition begins at 6 weeks of age in the cortex and 3-4 months of age in the hippocampus (Radde et al., 2006).

  3. X
    Gliosis at 6

    Activated microglia around Aβ deposits at 6 weeks as well as increased astrogliosis (Radde et al., 2006). Levels of CCL2 and TNFα increase at later ages (Lee et al., 2010).

  4. X
    Synaptic Loss at 10

    Dendritic spine loss around plaques reported to begin approximately 4 weeks after plaque formation and continue for several months (Bittner et al., 2012).

  5. X
    Changes in LTP/LTD at 35

    Hippocampal CA1 LTP normal at 4.5 months of age, but impaired at 8 and 15 months of age (Gengler et al., 2010).

  6. X
    Cognitive Impairment at 30

    Cognitive deficits in spatial learning and memory in the Morris water maze reported at 7 months (Serneels et al., 2009). Impaired reversal learning of a food-rewarded four-arm spatial maze task observed at 8 months (Radde et al., 2006).

Absent
  • Tangles at

    Phosphorylated tau-positive neuritic processes around plaques have been observed, but no mature tangles (Radde et al., 2006).

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN1 APP KM670/671NL (Swedish), PSEN1 L166P APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Amyloid plaque deposition starts at approximately 6 weeks in the neocortex. Amyloid deposits in the hippocampus appear at 3-4 months, and in the striatum, thalamus and brainstem at 4-5 months. Phosphorylated tau-positive neuritic processes have been observed in the vicinity of all congophilic amyloid deposits, but no fibrillar tau inclusions are seen.

 

Cognitive deficits in spatial learning and memory in the Morris water maze reported at 7 months. Impaired reversal learning of a food-rewarded four-arm spatial maze task at 8 months.

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APP/PS1/rTg21221

Observed
  1. X
    Neuronal Loss at 36

    Neuronal loss observed adjacent to plaques relative to more distal areas.

  2. X
    Plaques at 35

    Cortical plaques observed between 8-10 months. Plaques larger than in control mice not expressing human tau.

  3. X
    Gliosis at 37

    Increased astrocytosis adjacent to plaques relative to more distal areas.

  4. X
    Synaptic Loss at 40

    Decreased synapse density adjacent to plaques relative to more distal areas.

Absent
  • Tangles at

    No tangles. Aggregates of misfolded and phosphorylated tau observed between 8-10 months.

No Data
  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN1, MAPT APP KM670/671NL (Swedish), PSEN1: deltaE9 APP: Transgenic; PSEN1: Transgenic; MAPT: Knock-In Alzheimer's Disease

Tau accumulations, dystrophic neurites, astrocytosis, neuronal loss, and synapse loss were more pronounced adjacent to cortical plaques. Tangles were not observed.

No data.

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APPsw/0; Pdgfrβ+/-

Observed
  1. X
    Neuronal Loss at 39

    Progressive neuronal degeneration including reduced neurite density and reduced neuronal number in the cortex and hippocampus of APPsw/0; Pdgfrβ+/- mice at at nine months compared to age-matched APPsw/0; Pdgfrβ+/+ littermates.

  2. X
    Plaques at 39

    By 9 months of age APPsw/0;Pdgfrβ+/- mice have an elevated plaque load in the cortex and hippocampus compared with age matched APPsw/0;Pdgfrβ+/+. littermates. They also have extensive cerebral amyloid angiopathy.

  3. X
    Cognitive Impairment at 41

    At nine months, APPsw/0;Pdgfrβ+/- mice perform poorly on several hippocampal-dependent behavioral tests including burrowing, nest construction, and novel object recognition, compared with age-matched APPsw/0;Pdgfrβ+/+ littermates.

Absent
No Data
  • Tangles at

    Although mature neurofibrillary tangles were not observed by 9 months (the oldest age assessed), the mice develop significant tau pathology, including tau hyperphosphorylation in cortical and hippocampal neurons. Pre-tangle pathology is observed, including neuronal caspase-cleaved tau, and conformational changes as indicated by the conformation-specific antibody MC1.

  • Gliosis at

    Unknown.

  • Synaptic Loss at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PDGFRB APP KM670/671NL (Swedish) APP: Transgenic; PDGFRB: Knock-Out Alzheimer's Disease

Amyloid plaques; elevated brain interstitial human and murine Aβ due to reduced clearance of soluble Aβ, cerebral amyloid angiopathy, tau hyperphosphorylation and related pathology. Neurite loss and neuronal loss in the cortex and hippocampus.

Age-associated cognitive impairment as measured by hippocampal-dependent tasks, including nest building, burrowing, and novel object recognition.

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APPSwDI/NOS2-/-

Observed
  1. X
    Neuronal Loss at 52

    Significant neuron loss by 52 weeks in the hippocampus and subiculum, especially of neuropeptide Y neurons. Numerous Fluoro-Jade C+ neurons: 30% loss in the hippocampus, 35% loss in the subiculum (Wilcock et al., 2008).

  2. X
    Plaques at 49

    Aβ deposits by 52 weeks. Particularly dense Aβ immunoreactivity in the subiculum and thalamus, including in the cerebral microvessels (Wilcock et al., 2008).

  3. X
    Tangles at 49

    Extensive tau pathology by 52 weeks, including intraneuronal aggregates of hyperphosphorylated tau. Increased phosphorylated tau in bigenic mice compared to APPSwDI mice (Wilcock et al., 2008).

  4. X
    Cognitive Impairment at 53

    Impairments in spatial memory by 52-56 weeks as measured by the radial arm maze and the Barnes maze. Bigenic mice more impaired than APPSwDI (Wilcock et al., 2008).

Absent
No Data
  • Gliosis at

    Unknown.

  • Synaptic Loss at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, NOS2 APP KM670/671NL (Swedish), APP E693Q (Dutch), APP D694N (Iowa) APP: Transgenic; NOS2: Knock-Out Alzheimer's Disease

Plaques especially in the thalamus and subiculum. Aggregated, hyperphosphorylated tau tangles. Neuronal loss especially of NPY neurons in the hippocampus and subiculum. More severe pathology than Tg-SwDI alone.

Severe learning and memory deficits. Impaired spatial memory compared to Tg-SwDI as measured by the radial arm maze and the Barnes maze at 52-56 weeks.

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APP(Swedish) (R1.40)

Observed
  1. X
    Plaques at 59

    By 13.5 months homozygous mice develop both parenchymal and vascular amyloid deposits which first appear in the frontal cortex. No Aβ deposition at 5 months (Lehman et al., 2003).

  2. X
    Gliosis at 61

    Reactive astrocytes and microglia in 14-16 month old animals (Kulnane et al., 2001).

Absent
  • Tangles at

    No mature tangles, but some changes in phosphorylated tau.

  • Changes in LTP/LTD at

    Absent.

No Data
  • Neuronal Loss at

    Unknown.

  • Synaptic Loss at

    Unknown.

  • Cognitive Impairment at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP KM670/671NL (Swedish) APP: Transgenic Alzheimer's Disease

By 14-16 months, homozygotes have diffuse and compact Aβ deposits in the frontal cortex, by 18-20 months plaques throughout the cortex and olfactory bulb with occasional deposits in the corpus callosum and hippocampus. No tangles, but some changes in phosphorylated tau. Reactive astrocytes and microglia by 14-16 months.

Unknown.

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APPSwe (line C3-3)

Observed
  1. X
    Plaques at 104

    Some plaque formation at advanced age (24-26 months) (Savonenko et al., 2003).

Absent
  • Cognitive Impairment at

    Normal reference and working memory up to 12-14 months on congenic background (Savonenko et al., 2003).

No Data
  • Neuronal Loss at

    No data.

  • Tangles at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP KM670/671NL (Swedish) APP: Transgenic Alzheimer's Disease

Age-associated increase in Aβ40 and Aβ42 and some amyloid deposition at advanced age.

Congenic animals showed normal reference and working memory up to 12-14 months.

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APPSwe/PSEN1(A246E)

Observed
  1. X
    Plaques at 39

    By 9 months of age, amyloid plaques develop in the hippocampus and subiculum, later extending to the cortex (Borchelt et al., 1997). The striatum and thalamus are relatively spared out to 18 months of age. Amyloid pathology is more severe in female mice, with a greater amyloid burden measured at 12 and 17 months of age (Wang et al., 2003).

  2. X
    Gliosis at 52

    By one year of age, reactive gliosis is observed in the cortex and hippocampus and is associated with dystrophic neurites (Borchelt et al., 1997).

  3. X
    Cognitive Impairment at 48

    Age-associated cognitive impairment, as measured by the Morris water maze, was observed in 11 to 12-month-old males. Both acquisition and retention were impaired. No impairment at 3-4 months of age. At both time points mice performed normally on a position discrimination task in the T-maze (Puoliväli et al., 2002).

Absent
  • Neuronal Loss at

    There was no difference in neuronal numbers in the cingulate cortex compared with wild-type mice (Xiang et al., 2002).

  • Tangles at

    Not observed.

No Data
  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN1 APP KM670/671NL (Swedish), PSEN1 A246E APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Amyloid plaques by 9 months, starting in the hippocampus and subiculum. Plaques later develop in the cortex; the striatum and thalamus are relatively spared. Amyloid pathology is more severe in females. Dystrophic neurites and gliosis in the cortex and hippocampus.

Poor nest building. Reduced retention in a learned passive avoidance task. Increased immobility time in forced swim task. Age-associated impairment in acquisition and retention in the Morris water maze. No impairment in a position discrimination T-maze task.

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APPswe/PSEN1dE9

Observed
  1. X
    Neuronal Loss at 35

    Neuronal loss observed adjacent to plaques relative to more distal areas.

  2. X
    Plaques at 26

    Occasional Aβ deposits can be found by 6 months, with abundant plaques in the hippocampus and cortex by 9 months (Jankowsky et al., 2004) and a progressive increase in plaques up to 12 months (Garcia-Alloza et al., 2006).

  3. X
    Gliosis at 26

    Minimal astrocytosis at 3 months; significant astrocytosis by 6 months, especially in areas around plaques. Extensive GFAP+ staining at 15 months and later throughout the cortex (Kamphuis et al., 2012).

  4. X
    Synaptic Loss at 17

    In the B6 congenic mice, age-dependent loss of synaptophysin, synaptotagmin, PSD-95, and Homer immunoreactivity in the hippocampus by 4 months (Hong et al., 2016).

  5. X
    Changes in LTP/LTD at 13

    Transient long-term potentiation (t-LTP) is reduced by 3 months. The degree of impairment is not related to age from 3 to 12 months (Volianskis et al., 2008).

  6. X
    Cognitive Impairment at 52

    Impairment in the Morris water maze at 12 months, specifically during acquisition of the hidden platform sub-task and the probe trial, but not in the visible platform test (Lalonde et al., 2005). At 13 months the mice commit more errors in the Morris water maze, but not at 7 months (Volianskis et al., 2008).

Absent
  • Tangles at

    Not observed.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN1 APP KM670/671NL (Swedish), PSEN1: deltaE9 APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Occasional Aβ deposits by 6 months with abundant plaques in the hippocampus and cortex by 9 months and a progressive increase in plaques up to 12 months. No tangles. Decrease in synaptic markers and increase in complement immunoreactivity.

Cognitive impairment (e.g., deficits in spatial memory and contextual memory). Changes in spontaneous behavior (e.g., nest-building, burrowing). High incidence of seizures.

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APPSwe/PSEN1dE9

Observed
  1. X
    Plaques at 26

    Plaques are present in the hippocampus and cortex by 6 months of age.

  2. X
    Cognitive Impairment at 78

    Age-related cognitive deficits. Episodic memory appears to be more sensitive than reference memory. No differences at 6 months of age, but detectable at 18 months (Savonenko et al., 2005).

Absent
  • Tangles at

    Not observed.

No Data
  • Neuronal Loss at

    No data.

  • Gliosis at

    No data.

  • Synaptic Loss at

    No data.

  • Changes in LTP/LTD at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN1 APP KM670/671NL (Swedish), PSEN1: deltaE9 APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Elevated Aβ42 and plaques in the hippocampus and cortex. No tangles. Reduced cholinergic markers.

Age-related cognitive deficits; episodic memory more sensitive than reference memory. No differences at 6 months, but detectable at 18 months.

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APP(V642I)KI

Observed
  1. X
    Cognitive Impairment at 117
    Impairments at the water finding task at age 27-29 months, a test of long-term memory. No differences in the open field test of the elevated plus maze indicating no difference in general behavioral patterns, activity level, or emotional state.
Absent
  • Neuronal Loss at

    Absent.

  • Plaques at

    Absent.

  • Tangles at

    Absent.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP V717I (London) APP: Transgenic Alzheimer's Disease

Increased Aβ42(43) relative to Aβ40 at 29 months, but without neuritic plaques, neurofibrillary tangles, massive neuronal loss, or brain atrophy.

At 27-29 months mice displayed long-term memory deterioration. Acquisition of spatial memory is slightly affected, but no deterioration in short-term working memory. No difference in open field test or elevated plus maze suggesting no difference in overall behavioral patterns or activity levels.

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APP(V717I)

Observed
  1. X
    Plaques at 43

    Plaques start in the cortex and subiculum at ~10 months. Diffuse amyloid deposits and compact neuritic plaques at 13-18 months especially in the hippocampus and cortex, with occasional deposits in the thalamus and fimbria, external capsule, pontine nuclei, and white matter (Moechars et al., 1999). Prominent amyloid deposits in brain vessels after 15 months (Van Dorpe et al, 2000).

  2. X
    Gliosis at 43

    GFAP, microglial activation, and other markers of brain inflammation are elevated by 10 months.

  3. X
    Changes in LTP/LTD at 26

    Significant deficit in LTP in CA1 region of the hippocampus at 6 months.

  4. X
    Cognitive Impairment at 26

    From the age of 6 months, spatial and non-spatial orientation and memory deficits by Morris water maze and other tests. Also deficits in associative learning.

Absent
  • Neuronal Loss at

    Absent.

  • Tangles at

    Dystrophic neurites containing hyperphosphorylated tau, but no tangle pathology.

No Data
  • Synaptic Loss at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP V717I (London) APP: Transgenic Alzheimer's Disease, Cerebral Amyloid Angiopathy

Plaques start in the subiculum, spreading to the frontal cortex as dense and diffuse aggregates. Prominent amyloid deposits in brain vessels after 15 months. Microbleeds. Amyloid-associated inflammation. CSF Aβ42/Aβ40 ratio decreases from 15 months. Dystrophic neurites containing hyperphosphorylated tau, but no tangle pathology.

From the age of 6 months, spatial and non-spatial orientation and memory deficits by Morris water maze. Impaired associative learning. Increased agitation/anxiety from 8 weeks. Reduced ambulation, especially with age. Hyperactivity and aggression.

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APP(V717I) x PS1(A246E)

Observed
  1. X
    Plaques at 17

    Plaques start in cortex, hippocampus and subiculum at 4-6 months.

  2. X
    Gliosis at 20

    Elevated GFAP, microglial activation, and other markers of brain inflammation increase as of 4.5 months.

  3. X
    Changes in LTP/LTD at 26

    Significant deficit in LTP in CA1 region of the hippocampus at 6 months.

  4. X
    Cognitive Impairment at 22

    From the age of 5 months, spatial and non-spatial orientation and memory deficits by Morris water maze and other tests. Also deficits in associative learning.

Absent
  • Tangles at

    Dystrophic neurites containing hyperphosphorylated murine tau, but no tangle pathology.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN1 APP V717I (London), PSEN1 A246E APP: Multi-transgene; PSEN1: Transgenic Alzheimer's Disease, Cerebral Amyloid Angiopathy

Soluble, oligomeric Aβ at 2 months and increases with age. Amyloid plaques at 6-9 months, earlier than APP(V717I) single transgenics. Plaques start in the subiculum and spread to the frontal cortex. Amyloid-associated inflammation. CAA pathology at 8 months; microbleeds at 12-15 months. Dystropic neurites containing hyperphosphorylated tau, but no tangle pathology.

From the age of 5 months, spatial and non-spatial orientation and memory deficits by Morris Water Maze. Impaired associative learning, hyperactivity, anxiety, and aggression.

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Arc48 (APPSw/Ind/Arc)

Observed
  1. X
    Plaques at 9

    Parenchymal neuritic plaques by 2 months with prominent plaque deposition in the hippocampus by 3-4 months. Abundant mature thioflavin-S positive plaques with dystrophic neurites by 10-12 months (Cheng et al., 2007).

  2. X
    Gliosis at 13

    Reactive astrocytosis at 3-4 months in the dentate gyrus as demonstrated by GFAP immunoreactivity (Cheng et al., 2007).

  3. X
    Cognitive Impairment at 13

    At 3-4 months the Arc48 mouse was able to learn a task involving escape to a cued platform in the Morris water maze, but were impaired in the ability to use extramaze cues to navigate to the hidden platform (Cheng et al., 2007).

Absent
  • Tangles at

    Absent.

No Data
  • Neuronal Loss at

    Unknown.

  • Synaptic Loss at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP KM670/671NL (Swedish), APP V717F (Indiana), APP E693G (Arctic) APP: Transgenic Alzheimer's Disease, Cerebral Amyloid Angiopathy

Parenchymal neuritic plaques by 2 months accompanied by dystrophic neurites. Prominent hippocampal Aβ deposition by 3-4 months. Relatively low Aβ42/Aβ40 ratio. Comparable cerebrovascular amyloid deposition to J20.

At 3-4 months the Arc48 mouse was able to learn a task involving escape to a cued platform in the Morris water maze, but had an impaired ability to use extramaze cues to navigate to the hidden platform.

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ArcAβ

Observed
  1. X
    Plaques at 39

    Between 9 and 15 months of age β-amyloid plaques became prominent. Plaques had a characteristic dense core morphology which differed from the cotton wool-like structure of plaques seen with the Swedish mutation alone (Knobloch et al., 2007).

  2. X
    Changes in LTP/LTD at 15

    LTP is severely impaired in slices from 3.5 and 7.5 month old mice. LTP and basal synaptic transmission were normal in slices from one month old mice (Knobloch et al., 2007).

  3. X
    Cognitive Impairment at 26
    Cognitive impairment measured from the age of 6 months in the Morris water maze and Y-maze, as well as in active avoidance behavior (Knobloch et al., 2007).
Absent
  • Tangles at

    Absent.

No Data
  • Synaptic Loss at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP KM670/671NL (Swedish), APP E693G (Arctic) APP: Transgenic Alzheimer's Disease At 6 months intracellular punctate deposits of Aβ abundant in cortex and hippocampus, but overt β-amyloid plaques not apparent until 9-15 months. Severe CAA also present at this age with dense Aβ aggregates in blood vessels walls and spreading into the parenchyma.

Cognitive impairments from the age of 6 months measured in the Morris water maze and Y-maze.

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ARTE10

Observed
  1. X
    Plaques at 13

    Robust and reliable plaque pathology as early as 3 months in homozygotes, 5 months in hemizygotes. Plaques start in the anterior neocortex and subiculum, spreading to other brain regions (e.g. hippocampus, thalamus, amygdala). Congophilic dense-core plaques are abundant, with lower levels of diffuse plaques and some cerebral amyloid angiopathy.

  2. X
    Gliosis at 22

    Glial activation, including reactive astrocytes and activated microglia, is present in areas around plaques by 5 months of age in homozygous animals, later in hemizygotes.

  3. X
    Synaptic Loss at 13

    Decreased expression of synaptophysin mRNA in the brain by 3-4 months of age in both hemizygous and homozygous animals.

  4. X
    Cognitive Impairment at 52

    Select, paradigm-dependent, deficits in learning and memory, especially episodic memory, by 12 months in homozygous and hemizygous mice.

Absent
  • Neuronal Loss at

    Outright neuronal loss has not been documented, but substantial degeneration of dendritic arbors occurs by 10-14 months of age in hippocampal neurons.

  • Tangles at

    No tangles or neuropil threads, but some hyperphosphorylated tau by eight months in dystrophic neurites.

No Data
  • Changes in LTP/LTD at

    Unknown; however, hippocampal neurons exhibit substantial changes in electrophysiological properties by 10-14 months of age, including hyperexcitability in the form of increased firing of action potentials and a more efficient transition from solitary firing to bursting.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN1 APP KM670/671NL (Swedish), PSEN1 M146V APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Robust early plaque development (by 3 months in homozygotes, 5 months in hemizygotes), predominantly congophilic dense-core amyloid plaques surrounded by dystrophic neurites and gliosis. Some diffuse plaques and cerebral amyloidosis. No tau tangles. Neurons have reduced dendritic length, surface area, and branches.

Age-related learning and memory deficits, especially episodic memory, in select paradigm-specific tasks by 12 months.

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BRI-Aβ42 (BRI2-Aβ42)

Observed
  1. X
    Plaques at 13

    Detergent-insoluble amyloid-β and cored plaques as early as three months in the cerebellum. Variable forebrain pathology later with extracellular Aβ plaques in the hippocampus and entorhinal/piriform cortices by 12 months. Extensive congophillic amyloid angiopathy.

  2. X
    Gliosis at 13

    Plaque-associated reactive gliosis as measured by GFAP immunostaining.

Absent
  • Neuronal Loss at

    Absent.

  • Tangles at

    Absent.

  • Cognitive Impairment at

    On a mixed (C57/B6//C3H) background hemizygous mice have intact cognition as measured by fear conditioning at 12 months and 14-17 months despite accumulating amyloid.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
Transgenic Alzheimer's Disease, Cerebral Amyloid Angiopathy

Detergent-insoluble amyloid-β appearing with age and cored plaques as early as 3 months in the cerebellum. Variable forebrain pathology later with extracellular Aβ plaques in the hippocampus and entorhinal/piriform cortices at 12 months. Age-associated congophillic amyloid angiopathy. No tangles or neuronal loss.

On a mixed (C57/B6//C3H) background hemizygous mice have intact cognition as measured by fear conditioning at 12 months and 14-17 months despite accumulating amyloid.

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E2FAD

Observed
  1. X
    Plaques at 17

    Plaques develop in the subiculum and deep cortical layers by 4 months.

  2. X
    Gliosis at 26

    Microgliosis and astrocytosis in the subiculum and cortex at 6 months.

  3. X
    Synaptic Loss at 17

    Protein levels of  NMDA receptor subunits decreased from 2 to 6 months.

Absent
No Data
  • Neuronal Loss at

    No data.

  • Tangles at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    E2FAD mice had performance in learning and memory tasks comparable to E3FAD animals and better than E4FAD mice.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APOE, APP, PSEN1 APP KM670/671NL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V APOE: Knock-In; APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Amyloid plaques starting at 4 months and increasing with age. Gliosis and loss of synaptic proteins.

In the Y maze and Morris water maze, E2FAD mice performed better than E4FAD mice, and were comparabile to E3FAD mice.

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E3FAD

Observed
  1. X
    Plaques at 17

    Plaques develop in the subiculum and deep cortical layers by 4 months.

  2. X
    Gliosis at 26

    Microgliosis and astrocytosis in the subiculum and cortex at 6 months.

  3. X
    Synaptic Loss at 17

    Protein levels of  NMDA receptor subunits decreased from 2 to 6 months.

Absent
No Data
  • Neuronal Loss at

    No data.

  • Tangles at

    No data.

  • Changes in LTP/LTD at

    No data.

  • Cognitive Impairment at

    E3FAD mice had performance in learning and memory tasks comparable to E4FAD and E2FAD animals.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APOE, APP, PSEN1 APP KM670/671NL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V APOE: Knock-In; APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Amyloid plaques starting at 4 months and increasing with age. Gliosis and loss of synaptic proteins.

In the Y maze and Morris water maze E3FAD mice performed better than E4FAD mice, and were comparabile to E2FAD mice.

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E4FAD

Observed
  1. X
    Plaques at 17

    Plaques develop in the subiculum and deep cortical layers by 4 months.

  2. X
    Gliosis at 26

    Microgliosis and astrocytosis in the subiculum and cortex at 6 months.

  3. X
    Synaptic Loss at 17

    Decreased protein levels of PSD95 and NMDA receptor subunits by 4 months.

  4. X
    Cognitive Impairment at 8

    Modest learning deficits in the Morris water maze by 2 months. Progressive decrease in performance on learning and memory tasks. 

Absent
No Data
  • Neuronal Loss at

    No data.

  • Tangles at

    No data.

  • Changes in LTP/LTD at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APOE, APP, PSEN1 APP KM670/671NL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V APOE: Knock-In; APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Amyloid plaques starting at 4 months and increasing with age. Gliosis and loss of synaptic proteins. 

Age-dependent learning and memory deficits in the Y maze and Morris water maze.

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htau

Observed
  1. X
    Neuronal Loss at 43

    Decrease in cortical thickness and reduced cell number between 10 and 14 months of age. Increased ventricle size increased from age eight months to 18 months. Decrease in the thickness of the corpus callosum (Andorfer et al., 2005).

  2. X
    Tangles at 39

    Aggregated tau and paired helical filaments detectable at nine months by immunoelectron microscopy, although paired helical filaments of aggregated insoluble tau can be isolated from brain tissue as early as two months. Tau first redistributes from axons to cell bodies. Hyperphosphorylated tau begins to accumulate by six months, and increases further by 13 and 15 months (Andorfer et al., 2003).

  3. X
    Changes in LTP/LTD at 52

    In hippocampal slices, LTP induced by high frequency stimulation (HFS) was normal at four months but abolished by 12 months. LTP induced by theta burst stimulation (TBS) was normal at both ages. Paired-pulse ratio (PPR) was unaffected at four months, but increased at 12 months compared with controls, suggesting a decrease in probability of transmitter release (Polydoro et al., 2009).

  4. X
    Cognitive Impairment at 26

    Abnormal spatial learning in six-month-old mice compared with control mice (Phillips et al., 2011). Normal object recognition and spatial learning and memory by MWM at four months, but deficits by 12 months (Polydoro et al., 2009). Impaired burrowing relative to control mice occurs by four months (Geiszler et al., 2016).

Absent
No Data
  • Gliosis at

    Unknown.

  • Synaptic Loss at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT: Knock-Out; MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia

Age-associated tau pathology, including redistribution of tau to cell bodies and dendrites, phosphorylated tau, accumulation of aggregated paired helical filaments, and ultimately thioflavin-S positive neurofibrillary tangles. Pathology most severe in neocortex and hippocampus, and minimal in the brain stem and spinal cord. Some neuronal loss.

Normal object-recognition memory and spatial learning/memory (as assessed by the Morris Water Maze) at four months, but impaired at 12 months (Polydoro et al., 2009). 

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hTau-A152T

Observed
  1. X
    Neuronal Loss at 87

    Neuron loss in the hippocampus was observed by 20 months.

  2. X
    Gliosis at 17

    Astrocytosis, but no differences in microglia.

  3. X
    Cognitive Impairment at 74

    In the Morris water maze, performance was impaired after 17 months of age. Nest building was impaired at 10-14 months. Social interaction, anxiety, exploratory behavior, and motor functions were unaltered.

Absent
  • Tangles at

    Abnormal accumulations of soluble tau were observed, but not tangles or tangle-like structures.

  • Changes in LTP/LTD at

    Unchanged at 20 months.

No Data
  • Plaques at

    No data.

  • Synaptic Loss at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT A152T MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy

Tangles or dense tau inclusions not observed. Abnormal accumulations of soluble tau. Age-dependent neuronal loss was observed in the hippocampus.

Age-dependent learning and memory deficits in the Morris water maze. Nest building impaired. Social interaction, anxiety, exploratory behavior, and motor functions were normal.

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hTau-AT (hTau40-AT)

Observed
  1. X
    Neuronal Loss at 52

    Neuron loss in the hippocampus and cortex at 12 months.

  2. X
    Tangles at 13

    Tangles in hippocampus, cortex, and spinal cord starting at 3 months with age-dependent increases. Hyperphosphorylation, conformation changes, and mislocalization.

  3. X
    Gliosis at 43

    Astrocytosis and microgliosis at 10 months.

  4. X
    Synaptic Loss at 87

    Synaptophysin, but not PSD95, decreased in hippocampus and cortex at 12 months. By Golgi staining, spines unchanged in CA1 at 10 months, increased in CA3 at 12 months, and decreased in CA1 and CA3 at 16 months.

  5. X
    Cognitive Impairment at 70

    No change at 10 months but at 16 months deficits in learning and memory (Morris water maze).

Absent
  • Changes in LTP/LTD at

    Unchanged at 12 months.

No Data
  • Plaques at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT A152T MAPT: Knock-In Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy

Tangles in hippocampus, cortex, and spinal cord at 3 months with age-dependent increases. Tau hyperphosphorylation, conformation changes, and mislocalization observed. Age-dependent loss of synapses.

Age-dependent learning and memory deficits in the Morris water maze. Motor functions normal.

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hTau.P301S

Observed
  1. X
    Neuronal Loss at 13

    Neuronal loss starting at 3 months. Loss is especially prominent in the spinal cord with notable loss of superficial cortical neurons as well (Hampton et al., 2010).

  2. X
    Tangles at 17

    Neurofibrillary tangles detected as early as 4 months of age.

  3. X
    Gliosis at 22

    Astrocytosis, as measured by GFAP reactivity, in 6 month-old animals. Microglial activation in the brain stem and spinal cord of 5 month-old animals by OX42 staining (Bellucci et al., 2004).

  4. X
    Cognitive Impairment at 11

    Memory deficit starting at 2.5 months as assessed by the Morris water maze (Xu et al., 2014), but no deficit at 2 months (Scattoni et al., 2010).

Absent
  • Plaques at

    Absent.

No Data
  • Synaptic Loss at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT P301S MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy

Age-dependent hyperphosphorylation of tau and conformational changes leading to neurofibrillary tanglelike pathology in the cerebral cortex, hippocampus, brain stem, and spinal cord. Neurodegeneration, especially in the spinal cord, accompanied by astrocytosis.

Early motor impairment, including abnormal clasping and rotarod deficit at 4 months, with nearly complete deficit at 5 months. Deficits progress to severe paraparesis. Disinhibition and hyperactivity at 2 to 3 months.

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J20 (PDGF-APPSw,Ind)

Observed
  1. X
    Neuronal Loss at 12

    Cell loss varies by brain region. No significant neuronal loss was observed in the CA3 region of the hippocampus at 6, 12, 24 and 36 weeks of age nor in the CA1 region at 6 weeks; however, at 12, 24, and 36 weeks significant neuronal loss was observed in the CA1 region compared to age-matched wild-type animals (Wright et al., 2013).

  2. X
    Plaques at 22

    At 5-7 months of age diffuse amyloid-β plaques deposit in the dentate gyrus and neocortex. Amyloid deposition is progressive with widespread plaques by 8-10 months. Aβ puncta are deposited in the hippocampus as early as 1 month (Hong et al., 2016).

  3. X
    Gliosis at 24

    At 24 and 36 weeks a significant increase in the number of reactive GFAP+ astrocytes and CD68+ microglia was observed in the hippocampi of J20 mice compared to age-matched wild-type controls. No significant difference was observed at 6 and 12 weeks (Wright et al., 2013).

  4. X
    Synaptic Loss at 15

    Age-dependent loss of synaptophysin, synaptotagmin, PSD-95, and homer immunoreactivity in the hippocampus by 3 months; synapse loss was confirmed by electron microscopy. No significant difference was seen at 1 month (Hong et al., 2016).

  5. X
    Changes in LTP/LTD at 13

    Basal synaptic transmission is impaired between 3-6 months; extracellularly recorded field EPSPs at the Schaffer collateral to CA1 synapse in acute hippocampal slices were on average smaller in amplitude than those seen in wild-type mice. Significant deficits in LTP at the Schaffer collateral–CA1 synapse compared with control mice at 3-6 months (Saganich et al., 2006).

  6. X
    Cognitive Impairment at 16

    Deficits in spatial memory and learning appear as the mice age. As early as 16 weeks mice demonstrate spatial reference memory deficits as measured by the radial arm maze (Wright et al., 2013). By 6-7 months deficits appear in spatial memory retention and acquisition in the water maze (Palop et al., 2003).

Absent
  • Tangles at

    Absent.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP KM670/671NL (Swedish), APP V717F (Indiana) APP: Transgenic Alzheimer's Disease

Age-dependent formation of Aβ plaques. Dystrophic neurites associated with plaques. No tangles. Variable cell loss. Decrease in synaptic markers and increase in complement immunoreactvity.

Learning and memory deficits are age-dependent and may appear as early as 16 weeks. Hyperactivity and increased time in the open arm of the elevated plus maze than wild-type mice indicating lower levels of anxiety, but has not been universally replicated.

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JNPL3(P301L)

Observed
  1. X
    Neuronal Loss at 43

    Neuronal loss, especially in the spinal cord, most prominent in the anterior horn (Lewis et al., 2000).

  2. X
    Tangles at 20

    Neurofibrillary tangles develop in an age and gene-dose dependent manner; as early as 4.5 months in homozygotes and 6.5 months in heterozygotes. Tangles and Pick-body-like neuronal inclusions in the amygdala, septal nuclei, preoptic nuclei, hypothalamus, midbrain, pons, medulla, deep cerebellar nuclei and spinal cord (Lewis et al., 2000).

  3. X
    Gliosis at 43

    Astrogliosis (as measured by GFAP reactivity) in brainstem, diencephalon, and basal telencephalon by 10 months (Lewis et al., 2000).

Absent
  • Plaques at

    Absent.

No Data
  • Cognitive Impairment at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT P301L MAPT: Transgenic Frontotemporal Dementia, Progressive Supranuclear Palsy, Alzheimer's Disease

Age and gene-dose dependent development of neurofibrillary tangles as early as 4.5 months in homozygotes and 6.5 months in heterozyotes. Tangles and Pick-body-like inclusions in the amygdala, hypothalamus, pons, medulla, and spinal cord among other areas. Neuronal loss, especially in the spinal cord.

By 10 months, 90% developed motor and behavioral disturbances including limb weakness, hunched posture, decrease in grooming and vocalization.

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mThy-1 3R Tau (line 13)

Observed
  1. X
    Neuronal Loss at 34

    Neuronal loss occurred by 8-10 months as evidenced by decreased NeuN staining in the dentate gyrus and CA3 regions of the hippocampus. Neocortical volume also decreased.

  2. X
    Tangles at 34

    Pick-body like inclusions of aggregated tau appeared in the hippocampus and cortex by 8-10 months. Inclusions were positive for Bielchowsky silver stain but negative for Gallyas-silver stain and Thioflavin-S.

  3. X
    Gliosis at 35

    Astrogliosis was seen by 8-10 months in the neocortex and hippocampus. Some GFAP+ astrocytes also contained 3R tau.

  4. X
    Cognitive Impairment at 26

    By 6-8 months memory impairment was evident as a failure to habituate to a novel environment. This deficit was not present at 3-4 months. At 8-10 months, transgenics also took longer than wild-type mice to find the hidden platform in the Morris water maze.

Absent
  • Plaques at

    Absent.

No Data
  • Synaptic Loss at

    Synapto-dendritic damage manifested as reduced dendritic density, reduced MAP2 immunoreactivity, and accumulation of 3R tau in dendrites.

  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT L266V, MAPT G272V MAPT: Transgenic Frontotemporal Dementia, Pick's disease, Alzheimer's Disease

Accumulation of 3R tau in neurons of the cortex and hippocampus. Pick body-like tau aggregates and neuronal loss in the hippocampus and cortex. Astrogliosis, with some 3R tau in GFAP-positive astrocytes. Synapto-dendritic changes and mitochondrial pathology.

Age-related memory and motor deficits as assessed by habituation to a novel environment, the Morris water maze, and the round beam test.

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mThy1-hAPP751 (TASD41)

Observed
  1. X
    Plaques at 13

    Plaques start at 3-6 months in the frontal cortex and become widespread with age, affecting the piriform and olfactory cortices, hippocampus, and thalamus (Rockenstein et al., 2001; Havas et al., 2011).

  2. X
    Gliosis at 27

    Inflammation related to activated microglia (increased CD11) and reactive astrocytes (increased GFAP) is significant by 6 months and increases with age.

  3. X
    Synaptic Loss at 52

    Dystrophic neurites and synaptic loss starting at 12 months.

  4. X
    Cognitive Impairment at 26

    Cognitive impairment observed by 6 months by Morris Water Maze (Rockenstein et al., 2005).

Absent
  • Neuronal Loss at

    Absent.

  • Tangles at

    Absent.

No Data
  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP KM670/671NL (Swedish), APP V717I (London) APP: Transgenic Alzheimer's Disease

Age-dependent increases in Aβ40 and Aβ42, with Aβ42 > Aβ40. Plaques at an early age, starting at 3-6 months in the frontal cortex. At 5-7 months, size and number of plaques increased in the frontal cortex, and dense amyloid deposits appear in hippocampous, thalamus, and olfactory region.

Age-associated impairment in spatial memory and learning in the water maze task and habituation in the hole-board task, with significant deficits at 6 months of age. Some gender-specific differences in open field exploration.

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NSE-APP751

Observed
  1. X
    Plaques at 8

    Aβ deposits were observed as early as two months of age. These deposits were diffuse and extracellular and had a “cotton-like” appearance. Classic mature plaques were not observed.

  2. X
    Gliosis at 95

    Gliosis was noted in a single 22-month-old animal with extensive Aβ deposits (Higgins et al., 1994).

  3. X
    Cognitive Impairment at 52

    Deficits in spatial memory and learning appear as the mice age. At 12 months the mice demonstrate learning and memory deficits as measured by a water-maze task and in spontaneous alternation in a Y maze (Moran et al., 1995). At six months cognition is largely normal.

Absent
  • Neuronal Loss at

    Cell death was not formally assessed, however, overt neuronal death was not seen.

  • Tangles at

    Classic tangles were not observed, but aberrant tau immunoreactivity was observed as early as two months.

No Data
  • Synaptic Loss at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP: Transgenic Alzheimer's Disease

Age-dependent increase in Aβ deposits and tau immunoreactivity.

Learning and memory deficits are age-dependent as assessed on spontaneous alternation in a Y maze and in the water-maze task.

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PDAPP(line109)

Observed
  1. X
    Plaques at 26

    In heterozygous mice no plaque pathology at 4-6 months. At 6-9 months mice begin to exhibit deposits of human Aβ in the hippocampus, corpus callosum, and cerebral cortex. Plaques become more extensive with age and vary in size and structure including diffuse irregular plaques and compact cored plaques (Games et al., 1995).

  2. X
    Gliosis at 26

    GFAP-positive astrocytes and activated microglia associated with plaques (Games et al., 1995).

  3. X
    Synaptic Loss at 35

    Decreased synaptic density in the dentate gyrus as measured by synaptophysin immunoreactivity. Also decreased dendritic density as measured by MAP2 immunoreactivity (Games et al., 1995).

  4. X
    Changes in LTP/LTD at 17

    Alterations in LTP induced by theta burst stimulation at 4-5 months which is prior to plaque formation; although the potentiation immediately after TBS was comparable to control mice, the potentiation decayed more rapidly in PDAPP mice. Also paired pulse facilitation was enhanced. Responses to high frequency stimulation bursts were distorted (Larson et al., 1999).

  5. X
    Cognitive Impairment at 13

    Deficits in a variety of memory paradigms from a young age. Robust deficits in the radial arm maze at 3 months (deficits appear before amyloid plaque deposits). Object recognition, 6, 9-10 months. Operant learning, 3, 6 months (Dodart et al., 1999).

Absent
  • Neuronal Loss at

    Absent.

  • Tangles at

    No paired helical filaments or aggregates, but phosphorylated tau immunoreactivity is observed in dystrophic neurites after 14 months (Masliah et al., 2001).

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP V717F (Indiana) APP: Transgenic Alzheimer's Disease

Amyloid plaques in the hippocampus, cerebral cortex. Gliosis. Dystrophic neurites. Decreased synaptic and dendritic density in the hippocampus.

Deficits in a variety of memory paradigms from a young age. Deficits in the radial arm maze at 3 months (before plaques), object recognition, operant learning, spatial reference memory (starting at 3-4 months), cued fear conditioning at 11 months.

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PDGF-APP(WT) (line I5)

Observed
  1. X
    Synaptic Loss at 9

    By 2-4 months of age, there is a decrease in synaptophysin-immunoreactive presynaptic terminals compared to nonTg controls. Synaptophysin immunoreactivity decreases further with age.

Absent
  • Neuronal Loss at

    Not observed.

  • Tangles at

    Not observed.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP: Transgenic Alzheimer's Disease

Expression of human APP in the brain especially in the neocortex and hippocampus. No plaques up to 24 months.

Unknown.

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PLB1-triple (hAPP/hTau/hPS1)

Observed
  1. X
    Gliosis at 52

    Increased inflammation (GFAP labelling) detected at 12 months in cortex and hippocampus (Platt, unpublished observation).

  2. X
    Changes in LTP/LTD at 26

    Impairments in long-term and short-term hippocampal plasticity. LTP following theta-burst stimulation decayed faster and paired-pulse facilitation was reduced relative to wild-type mice at both six and 12 months of age. Synaptic transmission impacted at 12 months.

  3. X
    Cognitive Impairment at 22

    Social recognition memory was impaired by five months and further impaired by 12 months. Similarly, object recognition memory was impaired by eight months. Spatial learning impairments were seen later; at 12 months deficits in spatial acquisition learning were seen in the open field water maze that were not apparent at 5 months.

Absent
  • Neuronal Loss at

    Absent.

  • Plaques at

    Sparse plaques out to 21 months of age. Only marginally increased compared with wild-types and overall very low compared to over-expression models. However, Aβ accumulated intracellularly and also formed oligomers.

  • Tangles at

    No overt tangle pathology; however, hyyperphosphorylated tau accumulated in the hippocampus and cortex from six months of age.

No Data
  • Synaptic Loss at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, MAPT, PSEN1 APP V717I (London), APP KM670/671NL (Swedish), PSEN1 A246E, MAPT P301L, MAPT R406W APP: Multi-transgene; MAPT: Multi-transgene; PSEN1: Multi-transgene Alzheimer's Disease

Age-related neuropathology including intraneuronal and oligomeric Aβ accumulation and hyperphosphorylated tau in the hippocampus and cortex from six months. Minimal amyloid plaques up to 21 months. Subtle tau pathology, but no overt tangles. Cortical hypometabolism with increased metabolic activity in basal forebrain and ventral midbrain by FDG-PET/CT.

Cognitive deficits in recognition memory and spatial learning emerging between five and 12 months. Impairments in hippocampal plasticity.

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PLB4 (hBACE1)

Observed
  1. X
    Gliosis at 52

    Increased GFAP-positive astrocytes at 12 months of age in the dentate gyrus, CA1 region of the hippocampus, and the piriform cortex. Gliosis is suspected to begin earlier than 12 months.

  2. X
    Cognitive Impairment at 13

    Impaired spatial representation in a habituation task by 3 months of age. By 6 months, impaired learning and memory by a variety of tasks including the Y-maze, Morris water maze, and a test of the social transmission of food preference. These effects appear to be distinct from reduced motor activity and reduced anxiety.

Absent
  • Plaques at

    Plaques virtually absent, minimal small sparse plaques. However, prominent extracellular Aβ staining surrounding neuronal cell bodies, including Aβ multimers (e.g. Aβ*56 and Aβ hexamers).

  • Tangles at

    Preliminary analysis did not find abnormal phosphorylation or conformational changes in tau.

No Data
  • Neuronal Loss at

    Unknown.

  • Synaptic Loss at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
BACE1 BACE1: Transgenic Alzheimer's Disease

Elevated extracellular multimeric Aβ, including Aβ*56 and Aβ hexamers, in the absence of plaques. At 12 months of age, astrogliosis was observed in a region- and genotype-dependent manner, especially in the dentate gyrus, hippocampal CA1, and piriform cortex. No overt tau pathology.

Largely intact motor coordination and gait (Rotarod, CatWalk). Age-associated changes in multiple measures of learning and memory. Early deficits in habituation to a novel environment and semantic-like memory (three-four months). Impaired spatial learning and long-term reference (Morris water maze) and working memory (Y-maze) at six months, distinct from reduced locomotor activity and anxiety.

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PS1 cKO

Observed
  1. X
    Cognitive Impairment at 22

    Mild impairment of spatial learning and memory in the Morris water maze observed in 5 month-old mice (Yu et al., 2001).

Absent
  • Neuronal Loss at

    Absent.

  • Plaques at

    Absent.

  • Tangles at

    Absent.

  • Changes in LTP/LTD at

    Mice at 3-6 months of age exhibit normal paired-pulse facilitation, LTP, and LTD in the Schaffer collateral pathway of the hippocampus (Yu et al., 2001).

No Data
  • Gliosis at

    Unknown.

  • Synaptic Loss at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
PSEN1 PSEN1: Conditional Knock-out Alzheimer's Disease

Reduction in Aβ40 and Aβ42 peptides; accumulation of APP C-terminal fragments.

Subtle but significant deficits in long-term spatial memory in the Morris water maze.

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PS2APP

Observed
  1. X
    Plaques at 26

    Age-associated development of plaques: none at 3 months, overt Aβ deposition at approximately 6 months, with heavy plaque load in the hippocampus, frontal cortex, and subiculum at 10 months (Ozmen et al., 2009; Weidensteiner et al. 2009).

  2. X
    Gliosis at 26

    Gliosis at 6 months (personal communication, Laurence Ozmen).

  3. X
    Changes in LTP/LTD at 43

    A strong increase in LTP and post-tetanic potentiation induced by tetanic stimulation in hippocampal slices of 10 month-old animals compared to wild-type mice (Poirier et al., 2010).

  4. X
    Cognitive Impairment at 35

    Cognitive impairment is detected by the Morris water maze (probe trial 2) at 8 and 12 months of age, not at 3 months (personal communication Laurence Ozmen).

Absent
  • Tangles at

    Absent.

No Data
  • Neuronal Loss at

    Unknown.

  • Synaptic Loss at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN2 APP KM670/671NL (Swedish), PSEN2 N141I (Volga German) APP: Transgenic; PSEN2: Transgenic Alzheimer's Disease

Age-associated development of plaques: none at 3 months, overt Aβ deposition in the brain at approximately 6 months, with heavy plaque load in the hippocampus, frontal cortex, and subiculum at 10 months. Aβ deposits in blood vessels were sporadic, mainly in large vessels. Cerebral amyloid deposits correlate with levels of the human APP transcript at 12 months.

Cognitive impariment detected by the Morris water maze at 8 and 12 months of age, but not at 3 months.

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PS2APP (PS2(N141I) x APPswe)

Observed
  1. X
    Plaques at 39

    Rare amyloid deposits at 5 months, with consistent deposits in the subiculum and frontolateral cortices by 9 months. Plaques increase in number and distribution over time, spreading throughout the neocortex and hippocampus as well as the amygdala and thalamic and pontine nuclei (Richards et al., 2003).

  2. X
    Gliosis at 39

    An inflammatory response indicated by the presence of activated microglia and astrocytes begins around 9 months. The onset, distribution, and abundance of activated microglia and astrocytes correlate with Aβ deposition.

  3. X
    Cognitive Impairment at 35

    Age-associated cognitive impairment from 8 months with impaired acquisition of spatial learning in the water maze (Richards et al., 2003).

Absent
  • Tangles at

    Absent.

  • Changes in LTP/LTD at

    No difference in LTP in the dentate gyrus at 3 and 10 months compared to wild-type mice (Richards et al., 2003).

No Data
  • Neuronal Loss at

    Unknown.

  • Synaptic Loss at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN2 APP KM670/671NL (Swedish), PSEN2 N141I (Volga German) APP: Transgenic; PSEN2: Transgenic Alzheimer's Disease

Rare amyloid deposits at 5 months, with consistent deposits in the subiculum and frontolateral cortices by 9 months. Plaques increase in number and distribution with time, spreading throughout the neocortex and hippocampus as well as the amygdala and thalamic and pontine nuclei. The distribution and abundance of activated microglia and astrocytes correlate with Aβ deposition.

Mice develop age-associated cognitive impairment from 8 months with impaired acquisition of spatial learning in the water maze.

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PS/APP

Observed
  1. X
    Neuronal Loss at 79

    Neuronal loss in the CA1 region of the hippocampus has been reported at 22 months accompanied by reduced glucose utilization (Sadowski et al., 2004).

  2. X
    Plaques at 26

    Large amounts of Aβ accumulate in the cerebral cortex and hippocampus, starting around 6 months and increasing with age. Other brain regions are affected later. Both diffuse and fibrillar plaques form (Gordon et al., 2002).

  3. X
    Gliosis at 26

    GFAP-positive astrocytes appear first in the cortex in the vicinity of the developing Aβ deposits. Numbers increase with age, becoming confluent. Numbers of resting microglia (positive for complement receptor-3) increase in the vicinity of deposits at 6 months, but activated microglia (positive for MHC-II) are negligible before 12 months and more variable (Gordon et al., 2002).

  4. X
    Cognitive Impairment at 12

    Double and single transgenic mice had reduced spontaneous alternation performance in a “Y” maze, a test of spatial memory, at 12-14 weeks, before substantial Aβ deposition (Holcomb et al., 1998). Progressive age-related cognitive impairment is seen later in select tasks (e.g. water maze acquisition and radial arm water maze working memory)(Arendash et al., 2001).

Absent
  • Tangles at

    Neurofibrillary tangles are not associated with this model, but hyperphosphorylated tau is detected, starting at 24 weeks, appearing as punctate deposits near amyloid deposits in the cortex and hippocampus (Kurt et al., 2003).

No Data
  • Synaptic Loss at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN1 APP KM670/671NL (Swedish), PSEN1 M146L (A>C) APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Aβ accumulates in the cerebral cortex and hippocampus starting ~6 months and increasing with age. Other regions affected later. Deposition occurs in white matter,  cerebrovasculature, and grey matter in the form of diffuse and fibrillar plaques. Fibrillar deposits are associated with dystrophic neurites and GFAP-positive astrocytes at ~ 6 months with later microglial activation.

Progressive impairment between 5–7 and 15–17 months in some tests of cognitive performance, but not others. No change in anxiety levels.

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PS cDKO

Observed
  1. X
    Neuronal Loss at 9

    Significant increase (about 8-fold) in apoptotic neurons at 2 months of age, although the total number of cortical neurons is not significantly altered due to the low basal level of apoptosis in the cerebral cortex. By 4 months of age, the cumulative loss of cortical neurons reaches about 9 percent of all cortical neurons.

  2. X
    Gliosis at 17

    Astrogliosis and microgliosis; up-regulation of GFAP and other inflammatory markers are observed in the neocortex and hippocampus at 6 months, and this increases with age (Wines-Samuelson et al., 2010, Beglopoulos et al., 2004). 

  3. X
    Synaptic Loss at 26

    Reduction in synaptophysin immunoreactivity in hippocampal CA1 pyramidal neurons by 6 months. Reduction in dendritic spines by 9 months (Saura et al., 2004).

  4. X
    Cognitive Impairment at 9

    Deficits in the Morris water maze and contextual fear conditioning are mild at 2 months, but become more severe with age (Saura et al., 2004). 

Absent
  • Plaques at

    Absent.

  • Tangles at

    Tangles are absent, but hyperphosphorylation of tau has been reported in 9 month-old mice.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
PSEN1, PSEN2 PSEN1: Conditional Knock-out; PSEN2: Knock-Out Alzheimer's Disease

At 2 months the number of apoptotic neurons is elevated about 8-fold. By 6 months, about 18 percent of of cortical neurons are lost. Up-regulation of inflammatory markers and progressive astrogliosis and microgliosis in the neocortex and hippocampus.

Impairments in hippocampal learning and memory as indicated by Morris water maze and contextual fear conditioning evident by 2 months and worsens with age.

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rTg9191

Observed
  1. X
    Neuronal Loss at 9

    Expression of the tetracycline transactivator (tTA) resulted in reduced forebrain weight and smaller dentate gyri in rTg9191 mice compared to non-Tg littermates. This effect was also observed in mice expressing tTA alone, and is thought to be a developmental effect, as it was observed even in young mice (e.g., 2-6 months of age).

  2. X
    Plaques at 35

    Plaques emerge first in the cerebral cortex, starting around 8 months of age. This is followed by plaques in the hippocampus at 10.5 to 12.5 months of age. Some dense core plaques develop.

  3. X
    Gliosis at 104

    rTg9191 mice develop reactive gliosis (astrocytosis and microgliosis) in the vicinity of dense-core plaques by 24 months of age.

Absent
  • Tangles at

    Tangles are not observed, but hyperphosphorylated tau develops with age.

  • Cognitive Impairment at

    No transgene-related deficits seen in Morris water maze (4, 12, 21, 24 months of age) or fixed consecutive number test (23 months of age).

No Data
  • Synaptic Loss at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP KM670/671NL (Swedish), APP V717I (London) APP: Transgenic Alzheimer's Disease

Age-associated pathology in the cerebral cortex and hippocampus starting at 8 and 10½-12½ months of age, respectively. Gliosis and hyperphosphorylated tau in the vicinity of dense-core plaques. Fibrillar oligomeric species, e.g., Aβ dimers.

No transgene-related deficits seen in Morris water maze (4, 12, 21, 24, months of age) or fixed consecutive-number (23 months of age) tests.

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rTgTauEC

Observed
  1. X
    Neuronal Loss at 83

    Neuronal loss is detectable by 24 months of age in areas with transgene expression (e.g. layer II of the EC and parasubiculum), compared with age-matched mice expressing only tTA. Significant neuronal loss was not observed at 21 months (de Calignon et al., 2012).

  2. X
    Tangles at 78

    By 18 months of age, Gallyas silver-positive staining is observed, indicative of paired helical filaments. This is followed by thioflavin-S staining at 24 months. Tau pathology develops first in neurons of the medial EC expressing human tau, followed by neurons in the dentate gyrus, CA1 and CA2/3(de Calignon et al., 2012).

  3. X
    Gliosis at 104

    Microglial activation and astrogliosis by 24 months of age, in conjunction with axonal degeneration and neuronal loss (de Calignon et al., 2012).

  4. X
    Synaptic Loss at 104

    By 24 months of age pre- and post-synaptic densities were reduced in the middle third of the molecular layer of the dentate gyrus as measured by synapsin-1 and PSD-95 staining (de Calignon et al., 2012).

  5. X
    Changes in LTP/LTD at 70

    At 16 months of age, subtle differences in electrophysiological properties have been observed in the perforant pathway, including a decrease in LTP and an increase in the probability of neurotransmitter release (Polydoro et al., 2014).

  6. X
    Cognitive Impairment at 70

    Very mild and specific deficits in contextual fear conditioning at 16 months of age, but no deficits in the radial arm maze (Polydoro et al., 2014).

Absent
  • Plaques at

    Absent.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT P301L MAPT: Transgenic Frontotemporal Dementia, Alzheimer's Disease

Propagating tau pathology starting in the entorhinal cortex and spreading to regions functionally connected to the EC (e.g., dentate gyrus). Neurodegeneration and axonal degeneration, first in EC and parasubiculum. Gliosis and synaptic loss.

Subtle cognitive deficit in contextual fear conditioning, but not in the radial arm maze, at 16 months. Mild specific deficit in locomotor activity in the open field test.

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rTg(tauP301L)4510

Observed
  1. X
    Neuronal Loss at 24

    Decreased (~60%) CA1 hippocampal neurons by 5.5 months with significant loss in brain weight. Progressive loss of neurons and brain weight in 7 and 8.5 month mice with ~23% of CA1 pyramidal cells remaining at 8.5 months. Gross atrophy of the forebrain by 10 months.

  2. X
    Tangles at 17

    Pretangles as early as 2.5 months. Argyrophilic tangle-like inclusions in cortex by 4 months and in hippocampus by 5.5 months.

  3. X
    Synaptic Loss at 35

    Significant loss of dendritic spines at 8-9 months (~30% decrease in spine density in somatosensory cortex).

  4. X
    Cognitive Impairment at 11

    No significant abnormalities at 1.3 months but retention of spatial memory (Morris Water Maze) became impaired from 2.5 to 4 months. No significant motor impairments up to 6 months. Spatial memory improved when transgene suppressed by dox.

Absent
  • Plaques at

    Absent.

No Data
  • Changes in LTP/LTD at

    Electrophysiological properties of cortical neurons are altered as early as 1 to 3 months of age. In freely behaving mice, individual neocortical pyramidal neurons are less active as is the neocortical network as a whole. Hyperexcitability of cortical neurons has been observed in vitro, along with effects on resting membrane potential and action potential firing rates.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT P301L MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia

Argyrophilic tangle-like inclusions in cortex by 4 months and in hippocampus by 5.5 months. Decreased CA1 neurons (~60 percent) by 5.5 months. Gross forebrain atrophy by 10 months. The number of CA1 neurons stabilized after a brief (six to eight week) suppression of transgenic tau.

No significant abnormalities at 1.3 months in the Morris Water Maze. Spatial memory impairments by 2.5 to 4 months. No significant motor impairment up to 6 months of age. When the transgene was suppressed with dox at 2.5 months, spatial memory improved.

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TAS10 (thy1-APPswe)

Observed
  1. X
    Plaques at 52

    Fibrillar amyloid plaques develop by 12 months in the cortex and hippocampus.

  2. X
    Gliosis at 26

    Astrogliosis and microgliosis underway by 6 months of age in the dentate gyrus.

  3. X
    Synaptic Loss at 104

    TAS10 mice initially have more synapses than non-Tg mice; specifically, greater numbers of synapses per neuron were documented at 12 and 18 months of age. However, by 24 months of age, TAS10 mice have fewer synapses than non-Tg mice.

  4. X
    Cognitive Impairment at 26

    Deficits in spatial learning present by 6 months of age as measured by the Morris water maze. No difference from non-Tg at 2 months of age. Deficits in Y maze at 12 months. No deficit in fear conditioning up to 24 months of age.

Absent
  • Neuronal Loss at

    Qualitative difference in neuronal numbers at 24 months in specific regions of the hippocampus, but no significant neuronal loss.

  • Tangles at

    Absent.

  • Changes in LTP/LTD at

    At 12 to 14 months of age, deficits in basal synaptic transmission have been observed in the CA1 region, but short- and long-term synaptic plasticity are relatively normal (Brown et al., 2005).

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP KM670/671NL (Swedish) APP: Transgenic Alzheimer's Disease

Age-related accumulation of Aβ in the hippocampus and cortex leading to plaque deposition by 12 months of age. Early gliosis and dystrophic neurites, not limited to the vicinity around plaques. Changes in synaptic morphology and number, along with increased number of lysosomes.

Deficits in spatial memory prior to Aβ deposition, including deficits in the Morris water maze by 6 months Deficits in spontaneous alternation behavior in the Y maze by 12 months. No deficit in fear conditioning.

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TASTPM (TAS10 x TPM)

Observed
  1. X
    Plaques at 26

    Aβ begins to deposit at 3 months of age, with fibrillar plaques evident by 6 months in the cerebral cortex and hippocampus. Some vascular amyloid is also observed. Plaque pathology is more severe in female mice.

  2. X
    Gliosis at 28

    Greater numbers of reactive astrocytes and microglia by 6 months of age in the hippocampus and cortex, predominantly near amyloid plaques.

  3. X
    Cognitive Impairment at 26

    Age-dependent impairment in object recognition memory starting around 6 months of age for both sexes. No impairment at 3 to 4 months of age.

Absent
  • Neuronal Loss at

    Minimal neuronal loss up to 10 months of age. Some signs of loss in the immediate vicinity of plaques in the hippocampus (Howlett et al., 2008).

  • Tangles at

    Absent.

No Data
  • Synaptic Loss at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, PSEN1 APP KM670/671NL (Swedish), PSEN1 M146V APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

Aβ deposits beginning at 3 months of age, with fibrillar plaques by 6 months in the cerebral cortex and hippocampus. Some vascular amyloid. Plaques surrounded by dystrophic neurites and reactive glia. No tangles or neuronal loss. Female mice have more rapid and severe amyloid pathology.

Age-dependent impairment in object recognition memory starting around 6 months of age. 

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Tau35

Observed
  1. X
    Tangles at 35

    Abnormally phosphorylated tau detected at two months and by eight months tau was mislocalized and misfolded and dystrophic neurites were observed. Tangle-like structures observed in the hippocampus by 14 months.

  2. X
    Synaptic Loss at 61

    At 14 months synapsin1 protein levels were decreased but synaptophysin levels remained at wild-type levels.

  3. X
    Cognitive Impairment at 36

    In the Morris water maze, Tau35 had the same performance as wild-type animals at six months but developed progressive deficits by eight months. 

Absent
  • Gliosis at

    Gliosis was not observed at 14 months.

No Data
  • Neuronal Loss at

    Cell death was not formally assessed, however, overt neuronal death was not seen in the hippocampus.

  • Plaques at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT: Transgenic Progressive Supranuclear Palsy, Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy

Progressive tau pathology in the hippocampus, including abnormally phosphorylated and misfolded tau, mislocalized tau, and tangle-like structures. Dystrophic neurites.

Impaired spatial learning and memory in the Morris water maze. Early motor impairments, including abnormal limb clasping, Rotarod deficits and decreased grip strength.

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Tau4RTg2652

Observed
  1. X
    Cognitive Impairment at 13

    Deficits in spatial learning and memory as indicated by performance in the Barnes maze at multiple time points (3, 6, 11 months of age).

Absent
  • Neuronal Loss at

    Absent.

  • Plaques at

    Absent.

  • Tangles at

    Absence of mature neurofibrillary tangles, but extensive pretangle pathology throughout the brain (e.g. phospho-tau).

No Data
  • Gliosis at

    Unknown.

  • Synaptic Loss at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT: Transgenic Frontotemporal Dementia, Other Tauopathy, Alzheimer's Disease

Extensive pretangle pathology throughout the brain (e.g. phospho- tau) but no mature neurofibrillary tangles and only mild oligomeric tau, restricted to the CA1 region of the hippocampus. Dystrophic neurites and axonal pathology (spheroids). No overt neuronal loss.

Motor deficits develop with age, including decreased grip strength and impaired Rotarod performance. Cognitive deficits, indicative of impaired spatial learning and memory, as assessed by the Barnes maze.

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Tau609 (Tau 10 + 16)

Observed
  1. X
    Neuronal Loss at 65

    Significant loss of NeuN-positive neurons in layer II of the entorhinal cortex at 15 months, and in the hippocampal CA1 region at 24 months, compared with non-Tg controls. No difference in the hippocampus at 18 months.

  2. X
    Tangles at 65

    Gallyas silver-positive intracellular inclusions of hyperphosphorylated tau aggregates in the entorhinal cortex at 15 months, and in the hippocampus and cerebral cortex at 24 months, but not at 18 months.

  3. X
    Gliosis at 52

    At 12 months of age, Iba1-positive cells are observed. GFAP is observed at 24 months of age.

  4. X
    Synaptic Loss at 28

    Reduced synaptic density at 6 months of age in select hippocampal areas compared to non-Tg mice and those expressing wild-type human tau. Densities in other areas were comparable until later ages (i.e., 24 months).

  5. X
    Changes in LTP/LTD at 26

    Some changes in basal synaptic transmission and significant impairment of LTP evident by 6 months of age in some regions of the hippocampus.

  6. X
    Cognitive Impairment at 26

    Deficits in spatial reference memory by 6 months of age as measured by the Morris water maze. No difference from non-Tg littermates at 4 months of age.

Absent
  • Plaques at

    Absent.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT IVS10+16 C>T MAPT: Transgenic Frontotemporal Dementia, Alzheimer's Disease, Other Tauopathy

Aggregated tau in neurons of the entorhinal cortex, hippocampus, and cerebral cortex at advanced ages. Intraneuronal accumulation of tau oligomers in the hippocampus. Neuronal loss in the entorhinal cortex and hippocampus. Gliosis. Some hippocampal areas affected by age-related synaptic dysfunction and reduced synaptic density.

Impaired spatial reference memory as measured by the Morris water maze by 6 months of age. 

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TauC3 (Transgenic caspase-cleaved tau)

Observed
  1. X
    Synaptic Loss at 6

    Reduced levels of synaptic proteins as early as 1.3 months, including synaptophysin. Further reductions in 3 and 6-month-old animals.

  2. X
    Cognitive Impairment at 6

    Learning and memory impairments as early as 1.3 months in several behavioral tests including the Y-maze, passive avoidance, and novel object recognition.

Absent
  • Neuronal Loss at

    No significant neurodegeneration by 12 months of age.

  • Plaques at

    Amyloid plaques were absent.

  • Tangles at

    Neurofibrillary tangles were not observed; however, hyperphosphorylated tau occurred early in the form of oligomers and aggregates.

  • Gliosis at

    No significant astrogliosis in the hippocampus or cortex by 12 months of age.

No Data
  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia

No significant cell loss or astrogliosis in the brain. Age-dependent reduction in synaptic proteins (e.g. synaptophysin, PSD95) by 1.3 to 3 months of age. Hyperphosphorylated tau oligomers and aggregates.

Learning and memory deficits by 1.3 to 3 months of age, as assessed by the Y-maze and passive avoidance tests. No significant motor impairment.

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TauΔK280 ("Proaggregation mutant")

Observed
  1. X
    Tangles at 104

    Mature tangles are observed only at advanced age (>24 months), but extensive pre-tangle pathology develops with as little as three months of transgene expression. This includes mislocalization of tau to the somatodendritic compartment, conformational changes indicative of aggregation, and hyperphosphorylation (e.g. Ser 262, Ser 356).

  2. X
    Synaptic Loss at 57

    Electron microscopy showed a moderate decrease in spine synapses in the CA1 region of the hippocampus following 13 months of gene expression.

  3. X
    Changes in LTP/LTD at 52

    Impaired hippocampal LTP in the CA1 and CA3 areas.

  4. X
    Cognitive Impairment at 70

    Cognitive deficits in the Morris water maze and in passive-avoidance paradigms.

Absent
  • Neuronal Loss at

    Absent.

  • Plaques at

    Absent.

No Data
  • Gliosis at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT K280del MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia

Abundant pre-tangle pathology, but only rare mature tangles, and only at advanced ages. Tau pathology included mislocalization of tau to the somatodendritic compartment, aggregation, and hyperphosphorylation.

Unknown.

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Tau P301L

Observed
  1. X
    Tangles at 35

    Hyperphosphorylation, conformational changes, and aggregation of tau resulting in tangle-like pathology by 8 months.

  2. X
    Gliosis at 30

    Astrogliosis by 7 months.

  3. X
    Changes in LTP/LTD at 26

    Deficit in LTP in CA1 region of the hippocampus at 6 months, but enhanced LTP in the dentate gyrus at a young age (8-10 weeks).

  4. X
    Cognitive Impairment at 22

    Age-associated deficit in two cognitive tests that do not depend heavily on motor ability, the passive avoidance task (significant deficit starting at 5 months, but not 2 or 3 months of age) and a novel object recognition task (significant deficit at 9 months, but not at 2, 3, 5, or 7 months of age) (Maurin et al., 2014).

Absent
  • Plaques at

    Absent.

No Data
  • Neuronal Loss at

    Unknown.

  • Synaptic Loss at

    Unknown at advanced age. Young mice (1-2 months) have a significantly higher spine maturation index than controls. At 4-6 months, the spine maturation index remains high in the hippocampus, but is reduced to control levels in the cortex. Note, these results were generated using the progeny of Tau P301L x transgenic Thy1-YFP (Kremer et al., 2011).

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT P301L MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia

Pathologic hyperphosphorylation and conformational change of parenchymal tau in brain tissues starting at 7 months. Tangle-like pathology is mainly observed in the brain stem and spinal cord, and to a lesser extent in the midbrain and cerebral cortex. Age-dependent increase in total tau in CSF.

Age-associated deficits in a passive avoidance task (starting at 5 months) and a novel object recognition task (starting at 9 months). At a young age (~2 months) outperforms wild-type littermates in object recognition memory. Progressive motor impairment and reduced activity, accompanied by increased clasping of hind and then forelimbs around seven months.

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Tau P301S (Line PS19)

Observed
  1. X
    Neuronal Loss at 39

    Neuron loss in the hippocampus and entorhinal cortex by nine to12 months, as well as in the amygdala and neocortex becoming more severe by 12 months (Yoshiyama et al., 2007).

  2. X
    Tangles at 23

    Neurofibrillary tangles in the neocortex, amygdala, hippocampus, brain stem and spinal cord at six months with progressive accumulation (Yoshiyama et al., 2007).

  3. X
    Gliosis at 11

    Microgliosis at three months, especially in the white matter of the brain and spinal cord. Increased microgliosis by six months in white and gray matter of the hippocampus, amygdala, entorhinal cortex, and spinal cord. Microglial activation precedes astrogliosis (Yoshiyama et al., 2007).

  4. X
    Synaptic Loss at 13

    Synaptophysin immunoreactivity decreased progressively from three to six months in the CA3 region of the hippocamus. Impaired synaptic function (Yoshiyama et al., 2007).

  5. X
    Changes in LTP/LTD at 26

    Reduced LTP in the CA1 region of the hippocampus at six months. Altered basal synaptic transmission (smaller fiber volley amplitude, fEPSP slopes, and amplitudes) (Yoshiyama et al., 2007). Impaired hippocampal LTP as measured in freely moving mice (Lasagna-Reeves, 2016).

  6. X
    Cognitive Impairment at 27

    Impairments in spatial learning and memory ability in the Morris water maze in six-month-old animals (Takeuchi et al., 2011). Impaired memory in assays of contextual fear conditioning (Lasagna-Reeves 2016).

Absent
  • Plaques at

    Absent.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT P301S MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia

Neuron loss and brain atrophy by eight to 12 months, especially in the hippocampus and spreading to the neocortex and entorhinal cortex. Neurofibrillary tangles in the neocortex, amygdala, hippocampus, brain stem, and spinal cord. Neuroinflammation with microgliosis and astrocytosis.

Impairments in spatial memory and learning ability in Morris water maze. Paralysis at seven to 10 months associated with a hunched-back posture followed by feeding difficulties. About 80 percent mortality by 12 months with median survival of about nine months.

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TauPS2APP

Observed
  1. X
    Plaques at 17

    Rare amyloid plaques at 4 months, plaques become more abundant with age. By 8 months the number of amyloid plaques increases considerably in the subiculum and the CA1 region of the hippocampus (Grueninger et al., 2010).

  2. X
    Tangles at 70

    Abnormally phosphorylated tau is detectable at 4 months in both TauPS2APP and tau single transgenic mice especially in the subiculum, amygdala, and the CA1 region of the hippocampus. Tau pathology increases with age with numerous tangle-like deposits in the hippocampus confirmed by Gallyas silver staining at 16 months (Grueninger et al., 2010).

  3. X
    Cognitive Impairment at 17

    Impairment is not age-associated and does not progress from age 4 months to 12 months (Grueninger et al., 2010).

Absent
  • Neuronal Loss at

    No overt neuronal loss in the hippocampus at 16 months (Grueninger et al., 2010).

No Data
  • Gliosis at

    Unknown.

  • Synaptic Loss at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, MAPT, PSEN2 APP KM670/671NL (Swedish), MAPT P301L, PSEN2 N141I (Volga German) APP: Transgenic; MAPT: Transgenic; PSEN2: Transgenic Alzheimer's Disease

Phosphorylated tau accumulation in the subiculum and the CA1 region of the hippocampus at 4 months. Neurofibrillary tangles in these regions as well as the amygdala. Amyloid plaques. Dystrophic neurites and neuropil threads containing abnormally phosphorylated tau. No overt neuronal loss.

Impaired spatial learning in the Morris water maze at 4 months but impairment is not progressive between 4 and 12 months and appears to be independent of pathology.

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Tau R406W transgenic

Observed
  1. X
    Tangles at 78

    Congophilic tau inclusions in a subset of forebrain neurons around 18 months of age. Detected by Congo red, thioflavin S, and Gallyas silver stain.

  2. X
    Cognitive Impairment at 70

    Impairments in the contextual and cued fear conditioning test at 16–23 months compared with wild-type littermates. No detectable sensorimotor deficits.

Absent
  • Plaques at

    Absent.

No Data
  • Neuronal Loss at

    Unknown.

  • Gliosis at

    Unknown.

  • Synaptic Loss at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT R406W MAPT: Transgenic Frontotemporal Dementia, Alzheimer's Disease

Argyrophilic and congophilic tau inclusions in neurons of the forebrain with age. Detectable with Congo red, thioflavin-S and Gallyas silver stain. Congophilic tau inclusions also in the hippocampus and amygdala. Mainly straight tau filaments.

Impairments in contextual and cued fear conditioning at 16–23 months compared with wild-type littermates. No detectable sensorimotor deficits.

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TauRDΔK280 (“Proaggregation mutant”)

Observed
  1. X
    Neuronal Loss at 22

    Neuronal loss in the dentate gyrus (granule neurons) following 5 months of transgene expression. Shrinkage of the molecular layer of the hippocampus.

  2. X
    Tangles at 9

    Tau tangles and aggregates with as little as 2-3 months of transgene expression. Tangles start in the entorhinal cortex and amygdala and spread to the neocortex by 15 months. Heterogeneous tangle morphology, including flame-shaped.

  3. X
    Gliosis at 91

    Astrogliosis in the hilus region of the hippocampus after 21 months of transgene expression. Additional increases in GFAP-positive astrocytes in the entorhinal and piriform cortices.

  4. X
    Synaptic Loss at 41

    Hippocampal synaptic loss as indicated by multiple measures following 9.5 months of transgene expression. Reduced synaptophysin immunoreactivity and reduced number of spine synapses as measured by electron microscopy.

  5. X
    Changes in LTP/LTD at 43

    Multiple deficits in synaptic plasticity, including deficits in LTP and LTD, after 10 months of transgene expression. Functional changes are associated with structural synaptic changes, local calcium dysregulation, and a decrease in the synaptic vesicle pool.

  6. X
    Cognitive Impairment at 43

    Learning and memory impairments are apparent after 10 months of transgene expression as assessed by the Morris water maze and passive avoidance tasks.

Absent
  • Plaques at

    Absent.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT K280del MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia

Tau aggregates and tangles as early as 2-3 months after gene expression. Gallyas silver-positive neurons abundant in the entorhinal cortex and amygdala, spreading to the neocortex by 15 months. “Ballooned” neurons. Astrogliosis. Synaptic structural changes and reduced synaptic number. Hippocampal neuronal loss.

Reversible learning and memory deficits in the Morris water maze and passive avoidance test. No significant motor deficit, although slight reduction in Rotarod performance.

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Tau V337M

Observed
  1. X
    Neuronal Loss at 43

    Evidence of hippocampal neuronal degeneration in 10 month old animals: irregularly shaped neurons with tau pathology that stained with propidium iodide. As characteristics of apoptosis were not observed, the neurons were thought to be undergoing non-apoptotic atrophic degeneration (Tanemura et al., 2002).

  2. X
    Tangles at 48

    Fibrillar staining in the hippocampus of 11 month old animals by Congo red birefringence. Absent in 4 month old mice, indicating the formation of these neurofilament-like structures occurs between 4 and 11 months (Tanemura et al., 2001).

  3. X
    Changes in LTP/LTD at 65

    In hippocampal slices there was an attenuation of the amplitude of Schaffer collateral evoked hippocampal depolarization (Tanemura et al., 2002).

  4. X
    Cognitive Impairment at 48

    Behavioral abnormalities measured in 11 month-old mice. They spent more time in the open arms of the elevated plus maze and had greater overall locomoter activity. No differences in the Morris water maze compared with non-transgenic mice, suggesting the transgenic animals retain spatial recognition abilities (Tanemura et al., 2002).

Absent
  • Plaques at

    Absent.

No Data
  • Gliosis at

    Unknown.

  • Synaptic Loss at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT V337M (Seattle Family A) MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia

SDS-insoluble tau aggregates in hippocampus. Degenerating neurons in the hippocampus containing phosphorylated and ubiquitinated tau aggregates with β-sheet structure.

Higher overall spontaneous locomotion than non-transgenic littermates in elevated plus maze. No differences in the Morris water maze.

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TBA42

Observed
  1. X
    Neuronal Loss at 52

    Age-dependent neuronal loss in the CA1 region of the hippocampus. No difference from wild-type mice at 3 and 6 months of age, but approximately 35% loss at 12 months of age.

  2. X
    Plaques at 52

    Very rare extracellular Aβ deposits.

  3. X
    Gliosis at 52

    Marked gliosis in the hippocampus as measured by GFAP staining at 12 months.

  4. X
    Cognitive Impairment at 54

    Age-dependent deficits in working and spatial reference memory at 12 months, but not at 3 and 6 months.

Absent
  • Tangles at

    Absent.

No Data
  • Synaptic Loss at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP: Transgenic Alzheimer's Disease

Intraneuronal accumulation of Aβ peptides in the hippocampus by 3 months and in cerebellar nuclei by 6 months. Marked gliosis in the hippocampus by 12 months. Very rare extracellular Aβ deposits.

Age-dependent behavioral deficits, including working memory as assessed by the cross maze at 12 months, but not at 3 or 6 months. Early and persistent decrease in anxiety in the elevated plus maze. Comparable to wild-type in general motor coordination at 3 and 6 months as indicated by the balance-beam test, but impairment at 12 months.

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Tg2576

Observed
  1. X
    Plaques at 48

    Numerous parenchymal Aβ plaques by 11-13 months.

  2. X
    Gliosis at 43

    Increase in microglial density and size in plaque-forming areas of the brain including the hippocampus, frontal cortex, entorhinal cortex, and occipital cortex in 10-16 month old hemizygotes (Frautschy et al., 1998).

  3. X
    Synaptic Loss at 20

    Dendritic spine loss by 4.5 months In the CA1 region of the hippocampus (Lanz et al., 2003).

  4. X
    Changes in LTP/LTD at 22

    By 5 months, there was a decline in LTP in the dentate gyrus after perforant path stimulation compared to wild-type; impairment was not observed at 2 months (Jacobsen et al., 2006). Both the CA1 and dentate gyrus of aged mice (>15 months) are impaired (Chapman et al., 1999). Differences have been observed between the Schaffer collateral and mossy fiber pathways (Jung et al., 2011).

  5. X
    Cognitive Impairment at 26

    Impaired spatial learning, working memory, and contextual fear conditioning at <6 months although other studies have reported normal cognition at this age with progressive impairment by >12 months.

Absent
  • Neuronal Loss at

    Absent or very limited.

  • Tangles at

    Absent.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP KM670/671NL (Swedish) APP: Transgenic Alzheimer's Disease

Numerous parenchymal Aβ plaques by 11-13 months with some vascular amyloid. Oxidative lipid damage, astrogliosis and microgliosis. No tangles or neuronal loss.

Impaired spatial learning, working memory, and contextual fear conditioning reported at <6 months although other studies have reported normal cognition at this age with progressive impairment by >12 months.

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Tg2576/Tau(P301L) (APPSwe-Tau)

Observed
  1. X
    Plaques at 39

    Plaques develop gradually with age. No plaques at 5 months. Very few small plaques at 6 and 7 months. By 9 months plaques scattered throughout the cortex, hippocampus and amygdala, continue to increase at 12 months. Similar distribution as Tg2576.

  2. X
    Tangles at 13

    Neurofibrillary tangles in the spinal cord and pons as early as 3 months, but more consistent and numerous by 6 months. Tangles morphologically similar to those in JNPL3 mice but older bigenic female mice had a marked increase in neurofibrillary tangles in limbic areas by 6 months, especially the olfactory cortex, entorhinal cortex and amygdala (Lewis et al., 2001).

  3. X
    Gliosis at 13

    Reactive astrocytes and microglia as early as 3 months in the hippocampus as measured by GFAP and CD45. Increased astrocytosis with age especially in limbic areas with the most neurofibrillary tangles. Microglia especially concentrated around plaques at 9 and 12 months (Lewis et al., 2001).

Absent
No Data
  • Synaptic Loss at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP, MAPT APP KM670/671NL (Swedish), MAPT P301L APP; MAPT: Transgenic Alzheimer's Disease

Gradual appearance of plaques; by 9 months plaques are scattered throughout the cortex, hippocampus, and amygdala similar to Tg2576. Tau pathology more extensive than JNPL3. Astrocytosis and microgliosis.

Motor disturbances similar to JNPL3, with identical range in age of onset. Reduced vocalization and decreased grooming.

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Tg4-42

Observed
  1. X
    Neuronal Loss at 35

    Age- and dose-dependent neuronal loss in the hippocampus CA1 region of hemizygous and homozygous mice. Compared with wild-type, hemizygous mice had 38% neuronal loss at 8 months, and 49% loss at 12 months. No difference at 3 months.

  2. X
    Gliosis at 9

    Reactive microglia and astrocytes in the hippocampus starting at 2 months.

  3. X
    Synaptic Loss at 37

    Altered synaptophysin staining in the CA3 region of the hippocampus. More pronounced in homozygous mice than hemizygous mice at 8 months.

  4. X
    Cognitive Impairment at 35

    Spatial reference memory is impaired as assessed by Morris water maze at 8 months in homozygous mice and 12 months in hemizygous mice. Deficit is age-dependent and is not detected at 3 months. Impaired contextual fear conditioning at 12 months.

Absent
  • Plaques at

    Absent.

  • Tangles at

    Absent.

No Data
  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP: Transgenic Alzheimer's Disease

Aβ4-42 is dectable starting at two months, predominantly in the CA1 region of the hippocampus, but also in the occipital cortex, piriform cortex, striatum, and superior colliculus. Age- and dose-dependent hippocampal neuronal loss is seen in the CA1 region as well as microgliosis and astrogliosis.

Age-dependent spatial learning deficit as demonstrated in the Morris water maze, specifically, the absence of a preference for the target quadrant starting at eight months in homozygous mice and at 12 months in hemizygous mice. Impaired contextual fear conditioning.

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Tg-ArcSwe

Observed
  1. X
    Plaques at 22

    Extracellular amyloid plaque deposition starts at around 5-6 months of age (Lord et al., 2006) and is most consistently present in the cerebral cortex, hippocampus, and thalamus (Lillehaug et al., 2013).

  2. X
    Gliosis at 26

    Microgliosis and astrogliosis most prominent in the hippocampus, but also locally around deposits in the cerebral cortex and thalamus.

  3. X
    Cognitive Impairment at 17

    Transgene-dependent spatial learning impairment in the Morris water maze (4-8 months) (Lord et al., 2009) and in an Intellicage-based Passive Avoidance test (16 months)(Codita et al., 2010).

Absent
  • Neuronal Loss at

    Absent.

  • Tangles at

    Absent.

No Data
  • Synaptic Loss at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP KM670/671NL (Swedish), APP E693G (Arctic) APP: Transgenic Alzheimer's Disease, Cerebral Amyloid Angiopathy

Strong intraneuronal Aβ aggregation starting at 1 month and increasing with age. Extracellular amyloid plaque at 5-6 months, most consistent in the cerebral cortex, hippocampus, and thalamus. Congophilic parenchymal plaques are predominant, but some mice show marked CAA, particularly in the thalamus.

Mild spatial learning deficits at 4-8 months in Morris water maze and impaired functioning in a passive avoidance test at 16 months.

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TgCRND8

Observed
  1. X
    Neuronal Loss at 26

    Variable cell loss by region. No difference in overall cell count, but fewer hippocampal neurons at 6 months (Brautigam et al., 2012).

  2. X
    Plaques at 13

    Amyloid deposition progresses with age. Thioflavin S-positive amyloid deposits at 3 months; dense cored plaques and neuritic pathology by 5 months. Plaques appear first in the subiculum, amygdala and frontal cortex, spread to the dentate gyrus, the olfactory bulb, and later thalamus, cerebral vasculature, and striatum, followed by the cerebellum and brain stem (Chishti et al., 2001).

  3. X
    Gliosis at 13

    Microglia activation appears simultaneously with Aβ deposition, with only rare activated microglia at 9-10 weeks, but by 13-14 weeks microglia cluster around Aβ deposits in the cerebral cortex and hippocampus; numerous by 20 weeks. Robust astrogliosis slightly later with clusters of GFAP+ astrocytes emerging around plaques at 13-14 weeks (Dudal et al., 2004).

  4. X
    Synaptic Loss at 26

    Reduced synaptophysin immunoreactivity in the vicinity of plaques at 6 months (Adalbert et al., 2009).

  5. X
    Changes in LTP/LTD at 26

    In hippocampal slices from 6- to 12-month-old mice basal excitatory synaptic transmission (as assessed by I/O relationships) and LTP at CA1 are reduced in TgCRND8 mice compared with wild-type mice (Kimura et al., 2012).

  6. X
    Cognitive Impairment at 13

    Early impairment in acquisition and learning reversal in the reference memory version of the Morris water maze, present by 3 months (Chishti et al., 2001).

Absent
  • Tangles at

    Neurofibrillary tangles are absent (Chishti et al., 2001). Tau is hyperphosphorylated, nitrosylated and aggregated at 7-12 months especially in the neocortex, dentate gyrus, and the CA1 and CA3 areas of the hippocampus (Bellucci et al., 2007).

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP KM670/671NL (Swedish), APP V717F (Indiana) APP: Transgenic Alzheimer's Disease

Rapid, early plaque development, with thioflavin S-positive amyloid deposits at 3 months; dense cored plaques and neuritic pathology by 5 months. Plaques become more extensive with age. More Aβ42 than Aβ40. Activated microglia appear concurrently with plaques, whereas GFAP+ astrocytes follow later, about 13-14 weeks. Dystrophic neurites at 5 months .

Early impairment in acquisition and learning reversal in the reference memory version of the Morris water maze by 3 months. Cognitive deficits in the step-down inhibitory avoidance test at 7 months but not at 2 months. Similar to wild-type in motility, exploratory activity, or neuromuscular function at 7 months as evaluated by the rotarod, hole board and grip strength tests.

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Tg-SwDI (APP-Swedish,Dutch,Iowa)

Observed
  1. X
    Plaques at 13

    Hemizygotes progressively accumulate insoluble Aβ40 and Aβ42, especially within brain microvessels starting at 3 months. Amyloid-β deposits in the subiculum, hippocampus, and cortex at ~3 months. By ~6 months deposits become more numerous and appear in the olfactory bulb and thalamic region as well, with deposits throughout most of the forebrain by 12 months (Davis et al., 2004).

  2. X
    Gliosis at 26

    Pronounced increase in the number of GFAP-positive astrocytes and activated microglia with age (6-24 months) especially in the thalamus and subiculum and to a lesser extent in the cortex (Miao et al., 2005).

  3. X
    Cognitive Impairment at 13

    Impaired learning and memory in the Barnes maze task at 3, 9, and 12 months; beginning at 3 months took longer to find the escape hole. No difference in mobility, strength or coordination (Xu et al., 2007).

Absent
  • Tangles at

    Absent.

No Data
  • Neuronal Loss at

    Unknown.

  • Synaptic Loss at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP KM670/671NL (Swedish), APP E693Q (Dutch), APP D694N (Iowa) APP: Transgenic Alzheimer's Disease, Cerebral Amyloid Angiopathy, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch type

Hemizygotes progressively accumulate insoluble Aβ40 and Aβ42, especially within brain microvessels starting at 3 months. Fibrillar Aβ in micovessels around 6 months. Diffuse plaque-like deposits around 3 months in the subiculum, hippocampus and cortex. Aβ deposits throughout the forebrain by 12 months.

Impaired learning and memory in the Barnes maze task at 3, 9, and 12 months. Beginning at 3 months transgenic mice took longer to find the escape hole. No difference in mobility, strength or coordination.

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Tg-Swe

Observed
  1. X
    Plaques at 52

    Plaques are detectable at approximately 12 months and are heterogeneous in morphological structure and size, as well as in terms of fluorescence emitted when stained with luminescent polymers (conformational amyloid ligands)(Philipsson et al., 2009).

  2. X
    Gliosis at 52

    Microgliosis and astrogliosis are most prominent in the hippocampus, but also found locally around deposits in the cerebral cortex and in thalamus at approximately 12 months (Philipsson et al., 2009).

Absent
  • Neuronal Loss at

    Absent.

  • Tangles at

    Absent.

No Data
  • Synaptic Loss at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

  • Cognitive Impairment at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
APP APP KM670/671NL (Swedish) APP: Transgenic Alzheimer's Disease

Extracellular amyloid deposition begins at ~12 months. Intraneuronal Aβ aggregates at ~6 months. Extracellular pathology, both cerebrovascular amyloid angiopathy (CAA) and congophilic parenchymal plaques, mainly found in the cerebral cortex, hippocampus and thalamus. Aβ-burden in cerebral cortex is approximately 1.0% (at 12 months) and 2.8% (at 18 months).

Unknown.

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THY-Tau22

Observed
  1. X
    Neuronal Loss at 52

    Loss of cells in the CA1 region of the hippocampus from 12 months as measured by DAPI staining and Nissl/cresyl-violet (Schindowski et al., 2006). Also, a significant reduction in the number of choline acetyltransferase (ChAT)-immunopositive cholinergic neurons in the medial septum has been reported (Belarbi et al., 2011).

  2. X
    Tangles at 13

    Heterozygous animals develop tau pathology starting at 3-6 months. Pathology becomes more severe and widespread with age. Neurofibrillary tangle-like inclusions occur (Gallyas and MC1+) along with rare ghost tangles and paired helical filament-like structures (Schindowski et al., 2006).

  3. X
    Gliosis at 13

    Age-dependent increase in the number of GFAP+ astrocytes in the hippocampus (hilus, CA1, CA3), cerebral cortex, corpus callosum (Schindowski et al., 2006).

  4. X
    Changes in LTP/LTD at 39

    Altered paired pulse facilitation (PPF), a form of presynaptic short-term plasticity in 9-10 month old heterozygous animals: PPF increased at 10 ms. Also at this age, impaired maintenance of long term depression as compared with wild-type littermates (Van der Jeugd et al., 2011). Deficit in basal synaptic transmission in the hippocampus, but normal LTP (Schindowski et al., 2006).

  5. X
    Cognitive Impairment at 26

    Non-spatial memory affected as early as 6 months; spatial memory impaired only after 9 months (Van der Jeugd et al., 2013). Impaired appetitive responding (Lo et al., 2013).

Absent
  • Plaques at

    Absent.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT G272V, MAPT P301S MAPT: Transgenic Frontotemporal Dementia, Alzheimer's Disease

A variety of tau pathologies starting at 3 months, including neurofibrillary tangle-like inclusions, rare ghost tangles, and paired helical filament-like structures. Hyperphosphorylation of tau on many epitopes (e.g. AT8, AT100, AT180, AT270, 12E8, tau-pSer396, and AP422) and mild astrogliosis.

Increased anxiety and delayed learning from 3 months, and reduced spatial memory at 10 months. No changes in overall motor activity and no gross motor deficits. Increased depression-like and aggressive behavior, co-occurring with disturbances in nocturnal activity.

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TMHT (Thy-1 mutated human tau)

Observed
  1. X
    Tangles at 17

    Tangles at 4 months and progress with age.

  2. X
    Cognitive Impairment at 22

    Cognitive impairment by 5 months as measured by the Morris Water Maze.

Absent
  • Plaques at

    Absent.

No Data
Genes Mutations Modification Disease Neuropathology Behavior/Cognition
MAPT MAPT V337M (Seattle Family A), MAPT R406W MAPT: Transgenic Alzheimer's Disease

Increased total tau, and phosphorylated tau (Thr181, Ser199, Thr231) in amygdala and hippocampus starting at 3 months.

Spatial memory deficits starting at 5 months (Morris water maze). Olfactory deficits at 5 months (Buried food test). No motor deficits (rota rod, beam walk) or depressive behavior (forced swim test).

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PD-related Research Models

Phenotypes Examined

  • Neuronal Loss
  • Dopamine Deficiency
  • α-synuclein Inclusions
  • Neuroinflammation
  • Motor Impairment
  • Mitochondrial Abnormalities
  • Cognitive Dysfunction

When visualized, these phenotypes will distributed over a 18 month timeline demarcated at the following intervals: 3mo, 6mo, 9mo, 1yr, 15mo, 18mo+.

DJ-1 KO Rat

Observed
  1. X
    Neuronal Loss at 26

    Age-related decrease in tyrosine hydroxylase (TH)-positive dopaminergic neurons in the substantia nigra. 25 and 50 percent reduction at six months and eight months, respectively. No change in TH-immunoreactivity in the ventral tegmental area or striatum.

  2. X
    Motor Impairment at 17

    Abnormalities in gait and strength. As early as four months of age, KOs have abnormal paw positioning and a shorter stride. Overall decrease in muscle tone, particularly in the hind-limb extensor, leading to dragging hind limbs in some animals.

Absent
  • Dopamine Deficiency at

    Striatal dopamine level was increased 2-3 fold in KO rats compared to wild-type levels at eight months of age.

  • α-synuclein Inclusions at

    Staining for α-synuclein revealed no increase in the striatum or in any other brain region assessed.

No Data
  • Neuroinflammation at

    No data.

  • Mitochondrial Abnormalities at

    No data.

  • Cognitive Dysfunction at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
PARK7 (DJ1) PARK7 (DJ1): Knock-Out Parkinson's Disease

Age-related decrease in dopaminergic neurons in the substantia nigra; more than 50 percent reduction at eight months. Striatal dopamine and serotonin levels elevated 2-3fold over wild-type levels.

Abnormalities in gait and strength. First deficits measured at 4 months of age; abnormal paw positioning and a shorter stride. Weak hind limbs with some dragging. Coordination largely intact.

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LRRK2 G2019S Mouse (BAC Tg)

Observed
  1. X
    Dopamine Deficiency at 52

    Age-related decline in striatal dopamine content. Levels were decreased at 12 months of age, but not significantly different from controls at six months of age. Also, decreased dopamine metabolite homovanillic acid (HVA).

Absent
  • Neuronal Loss at

    No evidence of neuronal or other cell death in any brain region, including the cortex, striatum, and hippocampus. There was no difference in the number of dopaminergic neurons in the substantia nigra compared to littermate controls at six or 12 months.

  • α-synuclein Inclusions at

    No evidence of α-synuclein inclusions up to 18 months of age.

  • Motor Impairment at

    Behavior in hemizygous mice was comparable to littermate controls in terms of activity levels (open-field test) and coordination (beam-walk test) at 6 and 12 months.

No Data
  • Neuroinflammation at

    No data.

  • Mitochondrial Abnormalities at

    No data.

  • Cognitive Dysfunction at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
LRRK2 LRRK2 G2019S LRRK2: Transgenic Parkinson's Disease

Brain appears normal. No neuronal or cell death at 12 months. No increase in α-synuclein or ubiquitin levels or aggregation. Decreased striatal dopamine content, decreased evoked release.

Apparently normal behavior. No change in activity level or motor coordination at 12 months.

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LRRK2 G2019S Mouse (Tg)

Observed
  1. X
    Neuronal Loss at 83

    By 19-21 months of age, hemizygous mice lose about 18 percent of TH-positive dopaminergic neurons in the substantia nigra pars compacta and about 14 percent in the substantia nigra pars reticulata. At 1-2 months of age neuronal numbers were normal. The ventral tegmental area did not undergo abnormal neuronal loss.

  2. X
    Mitochondrial Abnormalities at 74

    At 17-18 months of age, the hemizygous mice exhibited abnormally high levels of condensed mitochondria in striatal neurons.

Absent
  • Dopamine Deficiency at

    At 14-15 months of age, hemizygous mice had normal levels of striatal dopamine, DOPAC, and HVA. However, in the olfactory bulb, levels of HVA and DOPAC were lower, but dopamine was unchanged.

  • α-synuclein Inclusions at

    At around 2 years of age, the mice did not exhibit abnormalities in α-synuclein in the ventral midbrain, striatum, or cerebral cortex.

  • Neuroinflammation at

    At around 2 years of age, the mice did not exhibit abnormalities in GFAP in the ventral midbrain, striatum, or cerebral cortex, compared to non-Tg controls.

  • Motor Impairment at

    No overt behavioral abnormalities up to 24 months of age. No change in locomotor activity or prepulse inhibition of the acoustic startle reflex.

No Data
  • Cognitive Dysfunction at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
LRRK2 LRRK2 G2019S LRRK2: Transgenic Parkinson's Disease

Age-dependent dopaminergic neuron degeneration in the substantia nigra. No reduction in striatal dopaminergic terminals or dopamine levels. No evidence of abnormal protein accumulation even at advanced ages. Abnormal mitochondria in neurons and accumulation of autophagic vacuoles.

No overt behavioral abnormalities up to 24 months of age. No change in locomotor activity or prepulse inhibition of the acoustic startle reflex.

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LRRK2 G2019S Rat (BAC Tg)

Observed
  1. X
    Motor Impairment at 35

    Mild abnormalities in motor behavior. Slightly more postural instability at eight months of age (but not at 4 and 12 months). Slightly more rearing events at 12 months, but not at younger ages.

Absent
  • Neuronal Loss at

    No overt loss of dopaminergic neurons in the substantia nigra out to 12 months of age.

  • Dopamine Deficiency at

    No change in striatal dopamine levels. No change in 3,4-dihydroxyphenylacetic acid (DOPAC) levels. No change in the rate of dopamine turnover. At 12 months of age transgenic rats exhibited higher levels of striatal homovanillic acid (HVA).

  • α-synuclein Inclusions at

    Under basal conditions no α-synuclein inclusions were observed. Inclusions could be induced by exogenous α-synuclein (e.g., viral transduction or fibril intracerebral injection). LRRK2 rats were more prone to inclusion formation under these conditions.

  • Neuroinflammation at

    No increase in Iba-1 positive microglia or GFAP-positive astrocytes in the substantia nigra at 12 months of age. However, iNOS expression was elevated in nigral dopaminergic neurons.

No Data
  • Mitochondrial Abnormalities at

    No data.

  • Cognitive Dysfunction at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
LRRK2 LRRK2 G2019S LRRK2: Transgenic Parkinson's Disease

No overt neurodegeneration out to 12 months of age. Elongated dopaminergic neurons. Elevated oxidative and nitrosative stress. No evidence of gliosis. No α-synuclein inclusions until challenged with exogenous α-synuclein. No change in dopamine levels.

Mild abnormalities in motor behavior. Slightly more postural instability at eight months of age (but not at four and 12 months). Slightly more rearing events at 12 months, but not at younger ages.

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LRRK2 KO Rat

Observed
Absent
  • Neuronal Loss at

    Under basal conditions, the number of TH-positive cells in the substantia nigra was comparable between Lrrk2 KO rats and wild-type rats. When challenged with LPS or α-synuclein overexpression, Lrrk2 KO rats developed significantly less neurodegeneration in the substantia nigra than wild-type rats.

  • Neuroinflammation at

    When challenged with LPS or α-synuclein overexpression, Lrrk2 KO rats show lower levels of pro-inflammatory CD68-positive myeloid cells in the substantia nigra than wild-type rats.

No Data
  • Dopamine Deficiency at

    No data.

  • α-synuclein Inclusions at

    No data.

  • Motor Impairment at

    No data.

  • Mitochondrial Abnormalities at

    No data.

  • Cognitive Dysfunction at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
LRRK2 LRRK2: Knock-Out Parkinson's Disease

Not observed. Protection against dopaminergic cell loss under conditions involving LPS or α-synuclein overexpression in the substantia nigra.

No data.

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LRRK2 R1441C Mouse (Tg - Conditional)

Observed
Absent
  • Neuronal Loss at

    In the substantia nigra pars compacta, there was no difference in the number of tyrosine hydroxylase(TH)-positive neurons or the total number of Nissl-positive neurons at 12 and 22 months.

  • Dopamine Deficiency at

    HPLC analysis of striata from 10-month-old mice revealed no significant differences in the levels of dopamine or its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA).

  • α-synuclein Inclusions at

    Immunohistochemical analysis of the brain at 22 months did not reveal abnormalities in α-synuclein, and no proteinaceous inclusions were seen.

  • Neuroinflammation at

    Immunohistochemical analysis of the brain at 22 months found GFAP and Iba1 immunoreactivity comparable to control levels.

  • Motor Impairment at

    Around 20 months of age, R26-LRRK2 mice behaved normally, exhibiting no deficits in locomotor activity (open-field test), motor coordination (Rotarod), or gait (digital catwalk system).

No Data
  • Mitochondrial Abnormalities at

    No data.

  • Cognitive Dysfunction at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
LRRK2 LRRK2 R1441C LRRK2: Transgenic Parkinson's Disease

No neurodegeneration in the brain. No proteinaceous inclusions of α-synuclein, ubiquitin, or tau. No reactive gliosis. No change in dopamine levels. Subtle morphological abnormalities in neuronal nuclei, including altered nuclear envelope.

No overt behavioral differences. Activity levels and Rotarod performance are normal into advanced age.

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LRRK2 WT Mouse (BAC Tg)

Observed
Absent
  • Motor Impairment at

    Not observed.

No Data
  • Neuronal Loss at

    No data.

  • Dopamine Deficiency at

    No data.

  • α-synuclein Inclusions at

    No data.

  • Neuroinflammation at

    No data.

  • Mitochondrial Abnormalities at

    No data.

  • Cognitive Dysfunction at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
LRRK2 LRRK2: Transgenic Parkinson's Disease

Overtly normal brain structure. Intact neurites.

No observed behavioral differences from wild-type mice at 10 months of age.

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Parkin KO Rat

Observed
Absent
  • Neuronal Loss at

    A small, non-significant reduction in dopaminergic neurons was observed in the substantia nigra at eight months of age.

  • Dopamine Deficiency at

    There were no differences in striatal dopamine levels at 4, 6, or 8 months compared to wild-type rats.

  • α-synuclein Inclusions at

    There was no increase in α-synuclein protein in the striatum or any other brain region assessed.

  • Motor Impairment at

    Parkin KO rats did not have behavioral deficits at any of the ages tested (4, 6, 8 months). Motor functioning, including gait performance on the Rotarod, was intact.

No Data
  • Neuroinflammation at

    No data.

  • Mitochondrial Abnormalities at

    No data.

  • Cognitive Dysfunction at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
PRKN (parkin) PRKN (parkin): Knock-Out Parkinson's Disease

Minimal pathology. A non-significant reduction in dopaminergic neurons in the substantia nigra. No differences in striatal dopamine levels.

Parkin KO rats exhibit normal behavior.

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Parkin Q311X Mouse (BAC Tg)

Observed
  1. X
    Neuronal Loss at 70

    Progressive loss of dopaminergic neurons in the substantia nigra. About 40 percent loss by 16 months of age with a corresponding decrease in dopaminergic projections to the striatum. Neurons in the ventral tegmental area were relatively spared.

  2. X
    Dopamine Deficiency at 83

    Surviving nigral neurons had reduced tyrosine hydroxylase expression. By 19-21 months, striatal concentrations of dopamine and the dopamine metabolite, 3,4-dihydrooxyphenylacetic acid (DOPAC), were decreased compared with non-Tg littermates.

  3. X
    Motor Impairment at 70

    Behavior was fairly normal at 3 months, but motor abnormalities were measured by 16 months of age, including hypoactivity and deficits in coordination and in motor response to sensory stimuli.

Absent
  • α-synuclein Inclusions at

    Inclusions were not observed at any age, however, the mice exhibit age-dependent accumulation of proteinase-K resistant endogenous α-synuclein in the substantia nigra.

No Data
  • Neuroinflammation at

    No data.

  • Mitochondrial Abnormalities at

    No data.

  • Cognitive Dysfunction at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
PRKN (parkin) Parkin Q311X PRKN (parkin): Transgenic Parkinson's Disease

Degeneration of dopaminergic neurons in the substantia nigra and nerve terminals in the striatum. Reduced dopamine in the striatum. Accumulation of proteinase-K resistant α-synuclein and oxidative protein damage.

Late-onset hypoactivity (about 16 months of age), other modest changes in motor behavior and coordination in tests that included traversing a beam or removing adhesive.

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PINK1 G309D (PINK1-/-) Mouse (KI)

Observed
  1. X
    Dopamine Deficiency at 39

    Decreased dopamine concentration in the striatum by 9 months of age.

  2. X
    Motor Impairment at 70

    At 16 months of age Pink1-/- mice exhibited decreased spontaneous locomotor activity. Strength and coordination were intact.

  3. X
    Mitochondrial Abnormalities at 13

    By 3 months of age the mice exhibited a mitochondrial import defect. This phenotype was more severe at 6 months and import was reduced nearly 50% by 12 months of age. By 6 months, ATP production, respiration, and mitochondrial membrane potential were also reduced.

Absent
  • Neuronal Loss at

    Neuronal loss was not observed at 18 months of age (total neuronal population and TH-positive subset).

  • α-synuclein Inclusions at

    No Lewy body-like inclusions of α-synuclein aggregates in the brainstem or substantia nigra, but the expression levels of alpha-synuclein are altered in brainstem/midbrain.

No Data
  • Neuroinflammation at

    No data.

  • Cognitive Dysfunction at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
PINK1 Pink1 G309D PINK1: Knock-In Parkinson's Disease

No neuronal loss. No Lewy bodies or α-synuclein aggregates, but alpha-synuclein expression change in brainstem/midbrain. Low dopamine levels. Mitochondrial dysfunction (e.g., reduced ATP, reduced respiratory activity).

Reduced spontaneous locomotor activity in open-field test. No difference in strength or coordination.

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PINK1 KO Mouse

Observed
Absent
  • Neuronal Loss at

    No decrease in the number of dopaminergic neurons in the substantia nigra at 2-3 months or 8-9 months of age. Neuronal morphology also grossly intact.

  • Dopamine Deficiency at

    Overall striatal levels of dopamine did not significantly differ from levels in wild-type mice at two to three months or eight to nine months of age.

  • Mitochondrial Abnormalities at

    No overt mitochondrial morphological defects.

No Data
  • α-synuclein Inclusions at

    No data.

  • Neuroinflammation at

    No data.

  • Motor Impairment at

    No data.

  • Cognitive Dysfunction at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
PINK1 PINK1: Knock-Out Parkinson's Disease

Overtly normal brain structure. Normal numbers of dopaminergic neurons in the substantia nigra at 8-9 months of age. Neuronal morphology grossly intact.

No data.

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Pink1 KO Rat

Observed
  1. X
    Neuronal Loss at 26

    Age-related decrease in tyrosine hydroxylase (TH)-positive dopaminergic neurons in the substantia nigra. Twenty-five and 50 percent reduction at 6 months and 8 months, respectively. No change in TH-positive cells in the striatum.

  2. X
    Motor Impairment at 17

    Abnormalities in gait, coordination, and strength. As early as four months of age, KO’s have abnormal paw positioning and a shorter stride. By 8 months, they exhibit 3-5-fold more foot slips on the balance beam. Overall decrease in muscle tone, particularly in the hind limb extensor, leading to dragging hind limbs.

Absent
  • Dopamine Deficiency at

    Striatal dopamine level was increased 2-3 fold in Pink1 KO rats compared with wild-type levels at eight months of age.

  • α-synuclein Inclusions at

    Staining for α-synuclein revealed no increase in the striatum or in any other brain region tested.

No Data
  • Neuroinflammation at

    No data.

  • Mitochondrial Abnormalities at

    No data.

  • Cognitive Dysfunction at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
PINK1 PINK1: Knock-Out Parkinson's Disease

Age-related decrease in dopaminergic neurons in the substantia nigra; greater than 50 percent reduction at eight months. Striatal dopamine and serotonin levels elevated 2-3-fold over wild-type levels.

Abnormalities in gait, coordination, and strength. First deficits measured at 4 months of age; abnormal paw positioning and a shorter stride, paw slips on balance bean. Weak hind limbs with dragging.

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α-synuclein A30P/A53T Mouse (Tg)

Observed
  1. X
    Dopamine Deficiency at 9

    Striatal dopamine concentrations were lower at all ages tested, including the earliest age, 2-3 months. Dopamine concentrations dropped with age, and levels of metabolites (e.g., DOPAC and HVA) were also lower in HM2 mice than non-Tg by 13-23 months of age.

  2. X
    Motor Impairment at 30

    At young age 2-3 months, HM2 mice were more active than non-Tg controls, but by middle age (7-9 months) they were less active. At advanced ages (13-23 months), they also exhibited impaired coordination as measured by the time it took to right themselves from an inverted wire screen.

Absent
  • Neuronal Loss at

    Not observed.

  • α-synuclein Inclusions at

    Inclusions were not observed at any age. Diffuse α- synuclein protein was both cytoplasmic and nuclear.

No Data
  • Neuroinflammation at

    No data.

  • Mitochondrial Abnormalities at

    No data.

  • Cognitive Dysfunction at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
SNCA SNCA A30P, SNCA A53T SNCA: Transgenic Parkinson's Disease

No dopaminergic cell loss. No α-synuclein inclusions. Morphological abnormalities in the dopaminergic system, including axonal and dendritic abnormalities, reduced dopamine concentration in the striatum.

More active as young adults, then hypoactive compared to non-Tg. Also reduced motor coordination in old age as measured by the time to right from an inverted wire screen.

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α-synuclein A53T Mouse (Tg)

Observed
  1. X
    α-synuclein Inclusions at 35

    Prior to motor deficits, these mice develop accumulations of α-synuclein in select neuronal populations, including the midbrain, cerebellum, brainstem, and spinal cord. The protein aggregates do not resemble Lewy bodies, but are thioflavin-S-positive, indicating fibrillar structure.

  2. X
    Neuroinflammation at 40

    In symptomatic mice, increased GFAP immunoreactivity was observed in select brain regions, including the dorsal midbrain, deep cerebellar nuclei, brainstem, and spinal cord. Cortex, hippocampus, and substantia nigra did not have increased reactivity compared with non-Tg controls.

  3. X
    Motor Impairment at 40

    These mice develop severe motor impairment starting around 9-16 months of age. The deficits start out with mild hyperactivity and progress to a wobbling movement, decreased activity, and ultimately paralysis and death.

Absent
  • Neuronal Loss at

    Overt neuronal loss was not reported in these mice.

  • Dopamine Deficiency at

    In symptomatic G2-3 mice, striatal dopamine and metabolites DOPAC and HVA were comparable to levels measured in non-Tg mice.

No Data
  • Mitochondrial Abnormalities at

    No data.

  • Cognitive Dysfunction at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
SNCA SNCA A53T SNCA: Transgenic Parkinson's Disease

No overt neuronal loss. No change in striatal dopamine levels. Region-specific neuronal accumulation of fibrillar α-synuclein, ubiquitin, and neurofilament-H, and accompanying astrocytosis.

Early hyperactivity followed by severe motor impairment, manifesting as wobbling, posturing, decreased spontaneous locomotor behavior, inability to navigate the Rotarod, and ultimately paralysis and death.

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α-synuclein A53T Mouse (Tg) on SNCA KO

Observed
  1. X
    Motor Impairment at 26

    By 6 months of age, homozygous mice became hypoactive, traveling less distance. This was not attributed to changes in exploratory behavior caused by anxiety. Also at 6 months, differences in performance on the accelerating Rotarod were seen.

Absent
  • Neuronal Loss at

    No evidence of neuronal cell loss in the substantia nigra at 11 and 18 months of age, including dopaminergic neurons (TH-positive neurons) and total neurons.

  • Dopamine Deficiency at

    No differences in striatal dopamine concentrations, or dopaminergic metabolites, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) at 11 and 18 months of age.

  • α-synuclein Inclusions at

    No evidence of Lewy body-like inclusions in the brain at any age. Likewise α-synuclein aggregates were not observed in the brain, although they did occur in enteric neurons in the gut.

No Data
  • Neuroinflammation at

    No data.

  • Mitochondrial Abnormalities at

    No data.

  • Cognitive Dysfunction at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
SNCA SNCA A53T SNCA: Transgenic; SNCA: Knock-Out Parkinson's Disease

No loss of dopaminergic neurons in the substantia nigra by 18 months of age. Rare dystrophic synapses in the hippocampus at advanced age, but no Lewy body-like pathology or α-synuclein aggregation in the brain. No change in striatal dopamine concentration.

Impaired performance on the Rotarod and reduced spontaneous locomotor activity in open-field test.

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α-synuclein E46K Rat (BAC Tg)

Observed
  1. X
    α-synuclein Inclusions at 52

    By 12 months of age, intracellular aggregates were observed in dopaminergic neurons of the substantia nigra and ventral tegmental area. Aggregates noted to be fairly small compared to those observed in PD brain. In the striatum and cortex α -synuclein accumulation appeared primarily in neuronal processes.

Absent
  • Neuronal Loss at

    No overt loss of dopaminergic neurons out to 12 months of age.

  • Dopamine Deficiency at

    No dopamine deficiency in the striatum at 12 months of age. No serotonin deficiency in the striatum. Dopamine metabolites dihydroxyphenylacetic acid and homovanillic acid were reduced by approximately 25 percent and transmitter turnover was decreased.

  • Motor Impairment at

    No overt motor differences out to 12 months of age, unless challenged with low-dose rotenone, upon which the rats exhibit bradykinesia, postural instability, and rigidity.

No Data
  • Neuroinflammation at

    No data.

  • Mitochondrial Abnormalities at

    No data.

  • Cognitive Dysfunction at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
SNCA SNCA E46K SNCA: Transgenic Parkinson's Disease

No overt neuronal loss. Accumulation of mutant α-synuclein in the brain, in the form of diffuse staining and intracellular aggregates. Aggregates were largely restricted to dopaminergic neurons of the substantia nigra and ventral tegmental area. Elevated nitrotyrosine in dopaminergic neurons.

No overt behavioral changes until challenged with low-dose rotenone, upon which the rats exhibit bradykinesia, postural instability, and rigidity.

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α-synuclein KO Mouse

Observed
  1. X
    Neuroinflammation at 16

    Microglia cultured from Snca KO brain were more reactive, ramified. They had vacuole-like structures. Snca KO microglia exhibited exacerbated response to LPS, with greater secretion of pro-inflammatory cytokines.

  2. X
    Motor Impairment at 26

    Motor function was largely intact. Normal performance on the Rotarod and in total distance travelled in the open field test. Subtle differences only (e.g., less rearing behavior than controls). They also spent less time in the center of the field, suggesting a possible anxiety-related phenotype.

  3. X
    Mitochondrial Abnormalities at 39

    Mitochondrial abnormalities include reduced levels of the mitochondrial phospholipid cardiolipin and reduced activity of electron transport chain complex I/III.

Absent
  • Cognitive Dysfunction at

    Learning and memory appeared intact at 6-10 months of age, based on performance in the Morris water maze and in tests of conditioned fear memory.

No Data
  • Neuronal Loss at

    No gross abnormalities in the brain.

  • Dopamine Deficiency at

    A possible modest reduction in striatal dopamine level, but highly variable from mouse to mouse.

  • α-synuclein Inclusions at

    No data.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
SNCA SNCA: Knock-Out Parkinson's Disease

No gross brain abnormalities. Electron microscopy revealed synaptic vesicle abnormalities in hippocampal neurons, i.e., fewer vesicles in the reserve pool.

Behavior is largely normal. Normal performance on the Rotarod. Subtle differences in locomotor activity (e.g., less rearing) but normal overall distance travelled. Learning and memory appear intact. Possible anxiety-like phenotype.

expand

α-synuclein KO Mouse (Conditional)

Observed
Absent
No Data
  • Neuronal Loss at

    No data.

  • Dopamine Deficiency at

    No data.

  • α-synuclein Inclusions at

    No data.

  • Neuroinflammation at

    No data.

  • Motor Impairment at

    No data.

  • Mitochondrial Abnormalities at

    No data.

  • Cognitive Dysfunction at

    Unknown.

Genes Mutations Modification Disease Neuropathology Behavior/Cognition
SNCA SNCA: Conditional Knock-out Parkinson's Disease

No data.

No data.

expand

ALS-related Research Models

Sex-specific differences

  • Cortical Neuron Loss
  • Lower Motor Neuron Loss
  • Cytoplasmic Inclusions
  • Gliosis
  • NMJ Abnormalities
  • Muscle Atrophy
  • Motor Impairment
  • Body Weight
  • Premature Death

C9-BAC500 (Brown model)

  • Absent
  • Absent
  • Observed
  • Absent
  • Absent
  • No Data
  • Absent
  • Absent
  • Absent

Not observed.

Not observed.

No cytoplasmic mislocalization, or aggregation of TDP-43 in the motor cortex. However, dipeptide repeats accumulated at advanced age and formed small perinuclear inclusion bodies positive for poly-GP.

No signs of increased activation of microglia or astrocytes in the brain or spinal cord.

No difference in denervation of neuromuscular junctions at 24 months of age. No difference in motor or sensory spinal nerve root axon number or morphology.

Muscle histology has not been reported, but no overt muscle atrophy was observed.

No overt motor deficit as measured by the Rotarod and grip strength.

Non-significant trend for male C9BAC mice to be heavier than non-Tg controls. Female data have not yet been reported.

Normal lifespan beyond 2 years in male mice. Female data have not yet been reported.

C9-BACexp (Baloh/Lutz model)

  • Absent
  • Absent
  • Observed
  • Absent
  • Absent
  • Absent
  • Absent
  • Absent
  • Absent

Not observed.

Not observed.

RNA foci throughout the nervous system starting at 3 months of age. Foci comprised of RNA transcripts in both the sense and antisense directions. Age-associated formation of dipeptide aggregates, e.g., poly-GP.

No increase in GFAP staining in the brain and spinal cord compared with non-Tg controls, even at 18 months of age.

Not observed.

Not observed.

No abnormalities in grip strength, Rotarod performance, or open-field testing at a young age (3 months) or advanced age (18 months), compared with non-Tg controls.

No abnormalities in body weight at a young age (3 months) or advanced age (18 months) compared with non-Tg controls.

Normal lifespan.

C9orf72 Knock-out

  • Absent
  • Absent
  • Absent
  • Absent
  • Absent
  • Absent
  • Observed
  • Absent
  • Absent

Not observed.

Not observed.

Not observed.

Not observed.

Not observed.

Not observed.

Reduced activity on open-field test. No abnormalities in grip strength or Rotarod performance.

Not observed.

Not observed.

C9ORF72(AAV)(G4C2)66

  • Observed
  • Absent
  • Observed
  • Observed
  • No Data
  • No Data
  • Observed
  • Observed
  • No Data

Compared with mice expressing 2-repeats, the 66-repeat mice had 17 percent fewer neurons in the cortex at 6 months of age and 11 percent fewer Purkinje cells in the cerebellum. At this age neurons in the hippocampus and thalamus were not affected.

At 6 months, neuronal loss in the spinal cord was not detected.

By 6 months, inclusions of C9RAN dipeptides were present in neurons of the cortex and hippocampus, and to a lesser extent in the cerebellum and spinal cord. Inclusions contained polyGA, polyGP, and polyGR dipeptides and were largely ubiquitin-positive.

Astrogliosis in the cortex by 6 months.

No data.

No data.

At 6 months, 66-repeat mice perform as well as 2-repeat mice on the Rotarod on the first day of testing. However, they fail to improve during subsequent trials, suggesting impairments in coordination and/or motor learning.

At 6 months females had a lower body weight than mice expressing 2-repeats. Body weight did not differ in males.

No data.

Endogenous Sod1 D83G

  • Observed
  • Observed
  • Absent
  • Observed
  • Observed
  • No Data
  • Observed
  • Observed
  • Observed

Neuronal numbers comparable to wild-type at 15 weeks, but about 20 percent loss of upper motor neurons by 29 weeks. Neurons in layer V of the motor cortex appeared selectively vulnerable.

Neuronal numbers comparable to wild-type at 6 weeks, but loss occurred by 15 weeks. The neuronal loss then stabilized; it was not more severe at 52 weeks of age.

Not observed.

Gliosis, of both astrocytes and microglia, was evident in the spinal cord by 15 weeks. It was further elevated at 52 weeks.

Denervation of a hindlimb muscle, the extensor digitorum longus, was detected by 52 weeks of age, and a decreased number of motor units in the EDL muscle.

Muscle atrophy was not reported, although changes to the muscle composition and histochemistry were observed.

Both male and female mice develop a variety of progressive motor symptoms. Grip strength was reduced at 6 weeks of age. Tremors developed by about 5 months of age. Rotarod performance was impaired, at 23 weeks in females and 67 weeks in males.

Homozygous mice, both male and female, showed reduced body weight by 4 weeks of age in contrast to wild-type littermates. Loss of excessive body weight was the primary factor leading to euthanasia.

Males reach end-stage sooner than females (495 ± 22 versus 588 ± 24 days). Animals were sacrificed when weight loss exceeded 20 percent of maximum weight, in accordance with animal-use guidelines. This is likely explained by the development of hepatocellular carcinomas due to SOD1 loss of function.

FUS-R521C

  • Absent
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed

No detectable loss of cortical neurons; however, neurons in the sensorimotor cortex show reduced dendritic complexity and reduced synaptic density.

No detectable difference in spinal motor neurons at P0. At P16, about 20% loss of ChAT-positive neurons in the anterior horn of cervical spinal cord. At P30-P60, about 50% loss of anterior horn neurons. Remaining motor neurons show reduced dendritic complexity and synaptic density.

Less than 10% of spinal motor neurons have cytoplasmic FUS inclusions.

Prominent increase in microgliosis and astrogliosis in the anterior horn of the spinal cord by end stage.

Reduced innervation of neuromuscular junctions in the diaphragm.

The majority of mice have severe skeletal muscle atrophy in the hindlimb by end stage.

Early postnatal motor impairment, including abnormal hindlimb clasping when lifted by the tail, gait abnormalities, and impaired Rotarod performance.

Early postnatal growth is retarded, and the mice experience progressive loss of body weight.

The majority of mice in the N1F1 generation reached end stage and were sacrificed by postnatal day 100. Mice in subsequent generations live longer: about 40% reach end stage by postnatal day 200.

FUSΔ14 (FUSd14)

  • Absent
  • Absent
  • Observed
  • Absent
  • No Data
  • No Data
  • Absent
  • No Data
  • No Data

Not observed.

Not observed.

Neuronal cytoplasmic inclusions were present by 3 months of age in the cerebral cortex. Inclusions occurred in about 20% of neurons and often co-labeled with ubiquitin.

No obvious astrogliosis or microglial activation at 3 months of age in the cerebral cortex.

No data.

No data.

When the mice were sacrificed at 3 months of age, they appeared healthy and displayed no obvious motor phenotype.

No data.

No data.

FusΔNLS

  • No Data
  • Observed
  • Observed
  • Observed
  • Observed
  • No Data
  • Observed
  • Absent
  • Absent

No data.

Approximately 30% reduction of motor neuron numbers in the dorsal spinal cord.

Ubiquitin pathology was observed in motor neurons, but p62 inclusions were not.

Slight increase in oligodendrocytes in the spinal cord white matter.

Fibrillation and fasciculation potentials were observed in the gastrocnemius or tibialis anterior muscles. There was also a reduction in compound muscle action potential amplitude.

No data.

By 10 months, mice demonstrated irregular walking patterns and reduced hang time on the inverted grid test. No deficits in grip strength or rotarod performance. Paralysis was not observed.

By 22 months, no weight loss was observed.

Life span was not altered.

hFUS (+/+) (PrP-hFUS)

  • Absent
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed

In the brain, overt neuronal loss was absent at end stage (~11 weeks).

By end stage (~11 weeks), homozygous mice had lost about 60 percent of α-motor neurons in the anterior horn of the lumbar spinal cord.

By end stage, cytoplasmic FUS inclusions, described as “granular” and “globular,” develop in the spinal cord of homozygous mice. Ubiquitin-positive inclusions also develop, but do not co-localize with FUS inclusions. Neurons in the brain also develop “granular” and “skein-like” FUS inclusions.

By end stage (~11 weeks), homozygous mice had microgliosis and astrogliosis in the anterior horn of the spinal cord and in the white matter of the dorsal columns. Reactive gliosis was absent in the brain, despite cytoplasmic inclusions of FUS in some neurons.

Homozygous mice had about 20 percent fewer functional motor units in the extensor digitorum longus muscle as estimated by neurophysiological assessment.

Muscle histology from end stage (~11 weeks) homozygous mice showed focal muscle atrophy in hindlimb muscles.

Homozygous mice exhibited motor symptoms at four weeks of age, starting with a tremor and mild signs of hindlimb dysfunction, including gait abnormalities. Motor symptoms progressed quickly, ultimately developing into hindlimb paralysis.

Homozygous mice fail to gain weight normally starting about four weeks of age. Their body weight declines in subsequent weeks, often precipitating euthanasia.

Homozygous mice were euthanized between 10 and 13 weeks of age when they developed severe motor impairment or lost 25 percent of their body weight. Average survival was 82 ± 12 days.

hFUS-P525L

  • No Data
  • Observed
  • Absent
  • Observed
  • Observed
  • Observed
  • Observed
  • No Data
  • Absent

No data.

Progressive loss of motor neurons at lumbar level 5.

No FUS inclusions were observed.

Astrocytosis and microgliosis were observed in the spinal cord.

Progressive denervation of hindlimb muscles. Decreased density of synaptic vesicles and mitochondria with normal morphologies. Altered electrophysiological properties.

Reduced fiber diameter in the tibialis anterior muscle.

Deficits in wire hang test at 360 days.

No data.

Not observed by 360 days.

hFUS-R521C

  • No Data
  • Observed
  • Absent
  • Observed
  • Observed
  • No Data
  • No Data
  • No Data
  • Absent

No data.

Progressive loss of motor neurons at lumbar level 5.

No FUS inclusions were observed.

Astrocytosis and microgliosis were observed in the spinal cord.

Progressive denervation of hind limb muscles. 

No data.

No data.

No data.

Not observed by 360 days.

hPFN1-G118V

  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed

At 202 days, there was a decrease in the number of corticospinal neurons of the motor cortex.

Progressive loss of ventral horn neurons from 165 through 202 days of age.

Spinal cord motor neurons had TDP-43 puncta.

Astrocytosis and microgliosis were observed in the spinal cord at end stage.

Denervation of gastrocnemius muscle at end stage. Muscle action potential also had reduced amplitude.

At 165 days, hind limb muscle atrophy was observed.

Progressive motor impairments began ~ 120 days. Mice demonstrated tremors, limb clasping, muscle weakness, gait abnormalities, as well as reduced locomotion and decreased performance on the Rotarod. 

Body weight peaked ~ 150 days and then progressively decreased.

Mice were sacrificed at an average of 202 days when they were unable to right themselves. Females on average reached 191 days while males attained 213 days.

hTDP-43ΔNLS

  • Observed
  • Absent
  • Absent
  • Observed
  • No Data
  • Absent
  • Observed
  • No Data
  • Absent

Severe neuronal degeneration in the dentate gyrus and deep layers of the neocortex. Other regions, such as the hippocampal CA1 subfield and olfactory bulb, were relatively resistant to neurodegeneration. Approximately 50 percent of dentate gyrus neurons were lost one month after the transgene was activated.

Not observed.

High levels of cytosolic TDP-43 but only very rare aggregates (observed in less than 1 percent of cortical neurons and even rarer in other brain regions, such as the hippocampus and striatum).

Severe astrogliosis and microgliosis in areas affected by neurodegeneration, including cortical and hippocampal regions, as well as the corticospinal tract.

Unknown.

Not observed.

Spastic motor impairment indicated by an abnormal clasping response as early as one week after transgene induction. A variety of motor deficits develop by one month after transgene induction, including impaired coordination on the Rotarod and decreased grip strength.

Unknown.

Not observed.

NEFH-tTA x hTDP-43ΔNLS

  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed

Decreased cortical thickness indicative of neuronal degeneration beginning at four weeks off dox. By end stage, rNLS8 mice had significantly smaller brains than non-Tg littermates.

rNLS8 lost motor neurons in the lumbar spinal cord by six weeks off dox.

Cytoplasmic inclusions of TDP-43 occur as early as one week off dox in neurons in the brain. Inclusions accumulate over time and are present in many brain regions, including the motor cortex. TDP-43 inclusions are relatively rare in the spinal cord. Ubiquitin-positive inclusions are also seen.

Astrogliosis develops in many brain regions, including layer V of the motor cortex.

Denervation of the hindlimb muscle tibialis anterior was detectable by four weeks off dox, that is, two weeks prior to detectable loss of lower motor neurons.

At end-stage, rNLS8 mice exhibit gross muscle atrophy of the hindlimb muscles tibialis anterior and gastrocnemius.

rNLS8 mice develop a variety of motor impairments, starting with a deficit in hindlimb clasping and a fine tremor in the forelimb and/or hindlimb. They also develop progressive loss of grip strength (as measured by the wire-hang test) and a progressive decline in coordinated movement and balance (as measured by the accelerating Rotarod).

Body mass peaked at approximately 7 weeks of age (i.e., two weeks off dox) and then progressively dropped. Excessive loss of body weight (>30% decrease from peak weight) often defined end-stage.

rNLS8 mice die prematurely. They reach end-stage 8-18 weeks off dox, with a median survival of 10.3 weeks off dox.

PFN1-C71G

  • Absent
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed

No neuronal loss in the cortex but neurodegeneration in medulla.

By 4 months there was a loss of cervical motor neurons and an increase in degenerating axons.

Cytoplasmic inclusions of PFN1, ubiquitin, and p62 in motor neurons around 6 months.

Microgliosis and astrogliosis observed in the dorsal horn by 5 months.

Denervation of gastrocnemius muscle occurs by 5 months.

Muscle atrophy in lower hind limb occurs by 6 months.

By 4 months, mice began showing minor gate changes and at 5-6 months they began demonstrating progressive deficits in Rotorod performance, vertical behaviors, and grip strength. 

Body weight peaked at 4-6 months and then progressively decreased.

Mice were sacrificed when they were incapable of locomotion following the paralysis of two or more limbs which occurred around 7 months of age.

PrP-hFUS (R495X)

  • Absent
  • Absent
  • Absent
  • No Data
  • Observed
  • No Data
  • Absent
  • No Data
  • Observed

Not observed.

Not observed.

Despite high levels of cytoplasmic FUS, neuronal inclusions were not observed.

No data.

A number of abnormalities were detected in the hindlimb musculature by electromyography (EMG). These phenotypes were detectable by 8-12 months of age and included fibrillation potentials, muscle denervation, and a reduction in the number of motor units.

No data.

Not observed.

No data.

Hemizygous mice sporadically developed intestinal swelling leading to premature death (mean survival 118 days). Homozygous mice were more severely affected (50 percent of the original cohort died around 59 days of age).

PrP-hFUS (WT)

  • No Data
  • No Data
  • Absent
  • No Data
  • Absent
  • No Data
  • Absent
  • No Data
  • Observed

No data.

No data.

Not observed.

No data.

Not observed.

No data.

Not observed.

No data.

Hemizygous mice die prematurely following a brief illness characterized by poor feeding. Mean survival of hemizygotes ~203 days.

SOD1 (G37R)

  • Absent
  • Observed
  • Absent
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed

Upper motor neuron loss was not observed, although vacuolization occurred in brainstem neurons.

Motor neurons in the spinal cord and brainstem degenerated with overt neuronal loss in the ventral horn in some regions of the spinal cord by 19 weeks. The degenerative process involved extensive vacuolization.

Not observed.

Astrogliosis occurs in the spinal cord by 11 weeks of age, becoming more severe with age.

Denervated endplates have been observed.

Loss of motor axons, denervated endplates, atrophy of muscle fibers, and fiber type grouping observed by end-stage.

Motor impairment at 4-6 months, beginning with reduced spontaneous movement, then tremors, limb weakness, and poor grooming. Eventual paralysis of the hindlimbs.

Loss of body weight is observed.

Mice survive about 6 to 8 months.

SOD1-G85R (hybrid)

  • No Data
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed

Unknown.

Extensive degeneration of large spinal axons coincident with the onset of clinical symptoms. By end stage, motor neurons in the ventral horn are lost.

Astrocytic inclusions occur early, about 6 months of age. The inclusions are immunoreactive for SOD1 and ubiquitin.

Astrogliosis and microgliosis are observed in the spinal cord starting around 6.5 months of age, and become more severe with age.

Denervation of muscle fibers is observed.

Hemizygous mice develop muscle weakness around 9 months of age, coincident with atrophy and denervation of muscle fibers.

Progressive motor impairment generally starting around 8 months with reduced grip strength in one hindlimb, rapidly spreading to other limbs and leading to paralysis within about two weeks.

Hemizygous mice start to lose weight at about 9 months of age.

End stage is characterized by paralysis at about 10 months of age.

SOD1-G93A (hybrid) (G1H)

  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed

Although outright upper motor neuron loss is absent or rare, degenerative signs (e.g., swollen neurites, Gallyas-positive aggregates, vacuoles, and neuritic spheroids) have been shown in motor regions of the cerebral cortex by five months of age.

Up to 50% loss of motor neurons in the cervical and lumbar segments of the spinal cord at end stage.

Inclusions accumulate in spinal motor neurons starting around 82 days of age. Inclusions generally take the form of spheroids or Lewy-body-like inclusions and commonly include a variety of neuronal intermediate filament proteins. TDP-43-positive inclusions are not present.

Gliosis, including the proliferation of reactive microglia and astrocytes, develops in parallel with motor neuron degeneration in the spinal cord.

Neuromuscular junctions degenerate around 47 days of age; fast-fatiguable motor neurons are affected first.

Longitudinal MRI has shown reduced muscle volume as early as 8 weeks of age. Atrophy is progressive. Skeletal muscle is affected, including limb and diaphragm.

Signs of motor impairment begin at about 3 months of age with a shaking tremor that leads to paralysis.

One of the first signs of illness is a slowing of growth and a plateauing of weight.

G1H mice reach end-stage disease by 5 months of age. Females typically survive longer than males.

TARDBP (A315T) (congenic)

  • No Data
  • Absent
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed
  • Observed

These mice lose corticospinal tract axons, but outright loss of cortical neurons has not been reported in the model. When crossed with a Thy-1YFP model to label layer 5 pyramidal neurons, mice expressing TDP-43 (A315T) had fewer neurons at 15 weeks of age than YFP littermate controls (Zhang et al., 2016).

Most studies reported no lower motor neuron loss. One study observed 20% loss of large ventral horn neurons, possibly dependent on diet and how long the mice live in an individual colony.

Ubiquitinated inclusions in the cytoplasm of spinal motor neurons and cortical layer V neurons. No evidence for cytoplasmic TDP-43 inclusions.

Reports of astrocytosis in cortical layer 5 and in the spinal cord, as well as microgliosis in the spinal cord.

Denervation of neuromuscular junctions at end stage (~11% on normal diet; ~20% loss on a gel diet).

Atrophy of gastrocnemius muscle (gel diet).

Deficits have been reported in nonspecific measures of strength and coordination such as the Rotarod (males and females) and hanging-wire test (males). A severely impaired gait (“swimming gait”) was observed in mice fed a gel diet.

Weight loss is a consistent feature. Potentially confounded by severe gut phenotype.

Survival is limited by severe gastrointestinal dysfunction and can be prolonged with a gel diet. Lifespan varies, but in general on a standard diet males live about 3 months and females about 6 months.

TARDBP (A315T) (hybrid)

  • Observed
  • Observed
  • Observed
  • Observed
  • No Data
  • Observed
  • Observed
  • Observed
  • Observed

By end-stage, neuronal numbers in layer 5 of the motor cortex are decreased with about 50 percent loss of corticospinal tract axons.

By end-stage, ~20% loss of motor neurons in the L3-L5 region of the spinal cord.

By end-stage, cytoplasmic inclusions of ubiquitinated proteins in layer 5 neurons of motor, sensory, and cingulate cortex. Ubiquitin aggregates in ventral horn neurons. TDP-43 inclusions were rare.

By end-stage, selective increase in GFAP immunoreactivity in cortical layer 5.

Unknown.

By end-stage, atrophic muscle fibers were observed.

Gait abnormalities around three months of age, developing into a characteristic “swimming gait” by four to five months.

Weight was comparable to non-Tg mice at birth. By 4.5 months transgenic mice began to lose weight.

Survival for about 5 months (154 ± 19 days) before dying spontaneously or being euthanized. It was not reported if this analysis includes males, females, or both.

TDP-43 (A315T)

  • Absent
  • Absent
  • Observed
  • Observed
  • No Data
  • No Data
  • Observed
  • No Data
  • Absent

Not observed.

Not observed.

Cytoplasmic accumulation of TDP-43 was observed by 10 months of age in the spinal cord. Furthermore, cytoplasmic aggregates were observed and often co-localized with ubiquitin. These inclusions are not detected at three months of age.

Progressive gliosis of both astrocytes and microglia, starting at a young age (by 3 months) in the brain and spinal cord.

Unknown.

Unknown.

At 38 weeks of age, mice develop impairments on the accelerating Rotarod relative to non-Tg littermates.

Unknown.

Not observed.

TDP-43 (A315T) (line 23)

  • Absent
  • Absent
  • Observed
  • Observed
  • No Data
  • Observed
  • Observed
  • Observed
  • Observed

Not observed.

Not observed.

Ubiquitin-positive cytoplasmic inclusions in neurons of the ventral horn and brainstem. Cytoplasmic aggregates of TDP-43 are largely absent, although rare phospho-TDP-43 inclusions were observed, especially at end-stage.

Mice exhibiting muscle weakness had astrocytosis in the ventral horn of the spinal cord.

Unknown.

Atrophy of muscle fibers in the quadriceps muscle of weak mice observed by day 44.

Progressive motor impairment, characterized by weakness, a decline in grip strength, and reduction in stride length. Weakness was usually more pronounced in the hindlimbs.

Progressive weight loss.

Line 23 mice survived about 2.5 months, mean survival 75 days. It was not reported whether this survival analysis includes males, females or both. Colony at Jackson Labs has longer mean survival.

TDP-43 (G348C)

  • Absent
  • Absent
  • Observed
  • Observed
  • Observed
  • No Data
  • Observed
  • No Data
  • Absent

Not observed.

Not observed.

Cytoplasmic accumulation of TDP-43 was observed by 10 months in the spinal cord. Cytoplasmic aggregates occurred and often co-localized with ubiquitin. These inclusions are not detected at 3 months of age.

Progressive gliosis of both astrocytes and microglia, starting at a young age (by 3 months) in the brain and spinal cord.

In 10-month-old mice, approximately 10% of NMJs in the gastrocnemius muscle were denervated, with another 20% partially denervated.

Unknown.

Performance on the Rotarod was comparable to non-Tg littermates until 36 weeks of age, and became progressively worse with age.

Unknown.

Normal lifespan.

TDP-43 (M337V)

  • Absent
  • Absent
  • Observed
  • Observed
  • No Data
  • No Data
  • Observed
  • Observed
  • Observed

Not observed.

Not observed.

TDP-43 protein was largely nuclear, although some cytoplasmic TDP-43 was also observed. Some mild cytoplasmic inclusions were reported.

Reactive astrocytes and activated microglia proliferate in the spinal cord and brainstem.

Unknown.

Unknown.

Body tremors apparent by day 21 and the mice had difficulty recruiting their hindlimbs, leading to an irregular gait pattern, described as “dragging.”

 

By one month of age, homozygotes have reduced body weight compared to non-Tg littermates.

 

70% mortality of homozygotes by around one month of age.

TDP-43 (M337V) (Mt-TAR6/6)

  • Observed
  • Observed
  • Observed
  • Observed
  • No Data
  • No Data
  • Observed
  • Observed
  • Observed

Severe neuronal loss in all CA regions of the hippocampus of homozygous mice. Neuronal loss was also observed in layer V cortical neurons and thalamic neurons.

Neuronal loss was observed in the spinal cords of homozygous mice.

Some homozygous mice developed cytoplasmic inclusions in layer V cortical neurons. These were often, but not always, ubiquitin–positive. They were not universally observed, even in end-stage mice.

Elevated astrogliosis and microgliosis compared with non-Tg controls, especially in the motor cortex and spinal cord. Gliosis in the hippocampus was seen at end stage.

Unknown.

Unknown.

Motor impairment developed quickly, by 11 days of age in homozygous mice, starting with an abnormal clasping reflex. They also develop a hunched posture, muscle twitches, and reduced mobility. Paralysis developed within days, leading to death. Hemizygotes do not develop motor symptoms until about one year of age, and impairment varied from mouse to mouse.

Early postnatal growth retardation in homozygous mice. By day 17 their average body weight is about half that of non-Tg controls.

Homozygous mice survived an average of just 17 days. In contrast, hemizygous Mt-TAR6 mice lived up to 24 months (average survival ~16.4 months).

TDP-43 (Prp)

  • Absent
  • Absent
  • Observed
  • Observed
  • No Data
  • Absent
  • Observed
  • Observed
  • Observed

Not observed.

Neuronal loss was not detected in spinal cords of homozygous mice as assessed by TUNEL staining and caspase-3 staining.

Cytoplasmic eosinophilic aggregates in spinal motor neurons by one month of age in homozygous mice.

Astrogliosis and microgliosis in the anterior horn of the spinal cord by one month of age.

Unknown.

Atrophy of the gastrocnemius muscle was not observed.

By day 21, homozygous mice displayed body tremors and mild gait impairment which progressed into a “swimming gait” and severe motor impairment.

 

Homozygotes diverge early from non-Tg littermates in terms of body weight, showing significantly reduced weight gain.

 

Homozygous mice were sacrificed at one to two months of age when they were unable to right themselves.

TDP-43 (Q331K)

  • No Data
  • Observed
  • Absent
  • Observed
  • Observed
  • No Data
  • Observed
  • No Data
  • No Data

Unknown.

Age-dependent loss of lower motor neurons in the lumbar spinal cord. Loss is detectable as early as 2 months of age and is more pronounced by 10 months.

TDP-43 in the brain and spinal cord was predominantly nuclear. Cytoplasmic TDP-43 aggregates were absent.

Elevated astrogliosis and microgliosis in the ventral horn of spinal cord by 10-12 months of age compared with non-Tg controls.

Reduction in neuromuscular junction endplates by 10-12 months of age. Remaining NMJs often had a “bleb-like” appearance.

Muscle fiber abnormalities including centralized nuclei and damage by 10-12 months of age.

Tremor, abnormal hindlimb clasping, impaired performance on the Rotarod were detectable starting around 3 months of age. Reduced grip strength occurred later.

Unknown.

Unknown.

TDP-43 (WT) (Elliott model)

  • Absent
  • Absent
  • Observed
  • No Data
  • No Data
  • Observed
  • Observed
  • Observed
  • Observed

Not observed.

Not observed.

Cytoplasmic ubiquitin-positive inclusions in skeletal muscle cells. Some TDP-43 inclusions, too.

Unknown.

Unknown.

An analysis of the quadriceps muscle, showed signs of myopathy, including variable muscle fiber size and disorganization of the muscle architecture.

Progressive motor impairment starting with external rotation of one hind limb followed by bilateral weakness and low muscle tone. Variable penetrance of this phenotype.

Progressive weight loss is part of the suite of symptoms in these mice.

The mean survival of hemizygous mice was 109 days. It was not reported if this value represents, males, females or both.

TDP-43 (WT) (Julien model)

  • Absent
  • Absent
  • Absent
  • Observed
  • Observed
  • No Data
  • Observed
  • No Data
  • No Data

Not observed.

Not observed.

Primarily nuclear localization of human TDP-43.

Gliosis, both microgliosis and astrogliosis, occur early in the brain and spinal cord. Reactive glia were detected as early as 3 months of age, with more by 10 months.

Some NMJ denervation was observed by 10 months of age. About 5% of NMJs at the gastrocnemius muscle were denervated, with another 20 percent partially denervated.

Unknown.

Decreased performance on the accelerating Rotarod at 42 weeks of age. Further impairment at 52 weeks.

Unknown.

Unknown.

TDP-43 (WT) (WT-TAR4/4)

  • Observed
  • Observed
  • Observed
  • Observed
  • No Data
  • No Data
  • Observed
  • Observed
  • Observed

In homozygous mice, quantitative loss of neurons occurs in the motor cortex compared with non-Tg littermates. Both superficial and deep cortical layers of the anterior cortex are affected.

By day 18, homozygous mice exhibited about 25 percent loss of motor neurons in the lumbar spinal cord compared with non-Tg littermates.

Homozygous mice developed cytoplasmic inclusions in the brain and spinal cord, many of which were ubiquitin-positive. A minority of inclusions co-labeled with TDP-43. Ultrastructural analysis revealed ubiquitin–negative cytoplasmic inclusions in anterior horn neurons to be abnormal accumulations of mitochondria.

Astrogliosis and microgliois especially in cortical layer V of the anterior cortex, including motor and somatosensory cortex, and in the spinal cord.

Unknown.

Unknown.

Homozygous mice exhibit an abnormal clasping reflex by postnatal day 14. Other early motor deficits include a shortened stride, a wide stance, and frequent stumbling. By day 18, reduced performance on the Rotarod. Complete paralysis occurs ~10 days after onset.

Size and weight of homozygous mice lag behind hemizygotes and non-Tg littermates.

Homozygous mice survive an average of just 24 days. In contrast, hemizygous mice survive to advanced age, although they die more prematurely than non-Tg mice, after 22 to 24 months.

ΔNLS-FUS

  • Observed
  • Absent
  • Observed
  • Observed
  • No Data
  • No Data
  • Observed
  • Observed
  • Observed

By 1 year, there was neuronal loss in the motor cortex.

Not observed at 1 year in the L5 anterior horn.

Ubiquitin- and p62-positive ΔNLS-FUS inclusions in motor cortex neurons.  

Microgliosis and astrocytosis were observed in the motor cortex.

No data.

No data.

Progressive motor impairments by 12 weeks. Mice demonstrated tremors, limb clasping, gait abnormalities, as well as decreased performance on the Rotarod and hanging wire tests.

Decreased by 48 weeks.

Approximately 50% mortality by 60 weeks of age.

ΔNLS-FUS x TDP-43(WT)

  • Observed
  • Absent
  • Observed
  • Observed
  • No Data
  • No Data
  • Observed
  • Observed
  • Observed

By 1 year, there was neuronal loss in the motor cortex.

Not observed at 1 year in the L5 anterior horn.

Ubiquitin- and p62-positive ΔNLS-FUS inclusions in motor cortex neurons.  

Microgliosis and astrocytosis were observed in the motor cortex.

No data.

No data.

Progressive motor impairments by 8 weeks. Mice demonstrated tremors, limb clasping, gait abnormalities, as well as decreased performance on the Rotarod and hanging wire test.

Decreased by 48 weeks.

Approximately 40% mortality by 60 weeks of age.

ALS-related Research Models

  • Sex-specific differences
  • Cortical Neuron Loss
  • Lower Motor Neuron Loss
  • Cytoplasmic Inclusions
  • Gliosis
  • NMJ Abnormalities
  • Muscle Atrophy
  • Motor Impairment
  • Body Weight
  • Premature Death

C9-BAC500 (Brown model)

Absent

Not observed.

Absent

Not observed.

Observed

No cytoplasmic mislocalization, or aggregation of TDP-43 in the motor cortex. However, dipeptide repeats accumulated at advanced age and formed small perinuclear inclusion bodies positive for poly-GP.

Absent

No signs of increased activation of microglia or astrocytes in the brain or spinal cord.

Absent

No difference in denervation of neuromuscular junctions at 24 months of age. No difference in motor or sensory spinal nerve root axon number or morphology.

No Data

Muscle histology has not been reported, but no overt muscle atrophy was observed.

Absent

No overt motor deficit as measured by the Rotarod and grip strength.

Absent

Non-significant trend for male C9BAC mice to be heavier than non-Tg controls. Female data have not yet been reported.

Absent

Normal lifespan beyond 2 years in male mice. Female data have not yet been reported.

C9-BACexp (Baloh/Lutz model)

Absent

Not observed.

Absent

Not observed.

Observed

RNA foci throughout the nervous system starting at 3 months of age. Foci comprised of RNA transcripts in both the sense and antisense directions. Age-associated formation of dipeptide aggregates, e.g., poly-GP.

Absent

No increase in GFAP staining in the brain and spinal cord compared with non-Tg controls, even at 18 months of age.

Absent

Not observed.

Absent

Not observed.

Absent

No abnormalities in grip strength, Rotarod performance, or open-field testing at a young age (3 months) or advanced age (18 months), compared with non-Tg controls.

Absent

No abnormalities in body weight at a young age (3 months) or advanced age (18 months) compared with non-Tg controls.

Absent

Normal lifespan.

C9orf72 Knock-out

Absent

Not observed.

Absent

Not observed.

Absent

Not observed.

Absent

Not observed.

Absent

Not observed.

Absent

Not observed.

Observed

Reduced activity on open-field test. No abnormalities in grip strength or Rotarod performance.

Absent

Not observed.

Absent

Not observed.

C9ORF72(AAV)(G4C2)66

Observed

Compared with mice expressing 2-repeats, the 66-repeat mice had 17 percent fewer neurons in the cortex at 6 months of age and 11 percent fewer Purkinje cells in the cerebellum. At this age neurons in the hippocampus and thalamus were not affected.

Absent

At 6 months, neuronal loss in the spinal cord was not detected.

Observed

By 6 months, inclusions of C9RAN dipeptides were present in neurons of the cortex and hippocampus, and to a lesser extent in the cerebellum and spinal cord. Inclusions contained polyGA, polyGP, and polyGR dipeptides and were largely ubiquitin-positive.

Observed

Astrogliosis in the cortex by 6 months.

No Data

No data.

No Data

No data.

Observed

At 6 months, 66-repeat mice perform as well as 2-repeat mice on the Rotarod on the first day of testing. However, they fail to improve during subsequent trials, suggesting impairments in coordination and/or motor learning.

Observed

At 6 months females had a lower body weight than mice expressing 2-repeats. Body weight did not differ in males.

No Data

No data.

Endogenous Sod1 D83G

Observed

Neuronal numbers comparable to wild-type at 15 weeks, but about 20 percent loss of upper motor neurons by 29 weeks. Neurons in layer V of the motor cortex appeared selectively vulnerable.

Observed

Neuronal numbers comparable to wild-type at 6 weeks, but loss occurred by 15 weeks. The neuronal loss then stabilized; it was not more severe at 52 weeks of age.

Absent

Not observed.

Observed

Gliosis, of both astrocytes and microglia, was evident in the spinal cord by 15 weeks. It was further elevated at 52 weeks.

Observed

Denervation of a hindlimb muscle, the extensor digitorum longus, was detected by 52 weeks of age, and a decreased number of motor units in the EDL muscle.

No Data

Muscle atrophy was not reported, although changes to the muscle composition and histochemistry were observed.

Observed

Both male and female mice develop a variety of progressive motor symptoms. Grip strength was reduced at 6 weeks of age. Tremors developed by about 5 months of age. Rotarod performance was impaired, at 23 weeks in females and 67 weeks in males.

Observed

Homozygous mice, both male and female, showed reduced body weight by 4 weeks of age in contrast to wild-type littermates. Loss of excessive body weight was the primary factor leading to euthanasia.

Observed

Males reach end-stage sooner than females (495 ± 22 versus 588 ± 24 days). Animals were sacrificed when weight loss exceeded 20 percent of maximum weight, in accordance with animal-use guidelines. This is likely explained by the development of hepatocellular carcinomas due to SOD1 loss of function.

FUS-R521C

Absent

No detectable loss of cortical neurons; however, neurons in the sensorimotor cortex show reduced dendritic complexity and reduced synaptic density.

Observed

No detectable difference in spinal motor neurons at P0. At P16, about 20% loss of ChAT-positive neurons in the anterior horn of cervical spinal cord. At P30-P60, about 50% loss of anterior horn neurons. Remaining motor neurons show reduced dendritic complexity and synaptic density.

Observed

Less than 10% of spinal motor neurons have cytoplasmic FUS inclusions.

Observed

Prominent increase in microgliosis and astrogliosis in the anterior horn of the spinal cord by end stage.

Observed

Reduced innervation of neuromuscular junctions in the diaphragm.

Observed

The majority of mice have severe skeletal muscle atrophy in the hindlimb by end stage.

Observed

Early postnatal motor impairment, including abnormal hindlimb clasping when lifted by the tail, gait abnormalities, and impaired Rotarod performance.

Observed

Early postnatal growth is retarded, and the mice experience progressive loss of body weight.

Observed

The majority of mice in the N1F1 generation reached end stage and were sacrificed by postnatal day 100. Mice in subsequent generations live longer: about 40% reach end stage by postnatal day 200.

FUSΔ14 (FUSd14)

Absent

Not observed.

Absent

Not observed.

Observed

Neuronal cytoplasmic inclusions were present by 3 months of age in the cerebral cortex. Inclusions occurred in about 20% of neurons and often co-labeled with ubiquitin.

Absent

No obvious astrogliosis or microglial activation at 3 months of age in the cerebral cortex.

No Data

No data.

No Data

No data.

Absent

When the mice were sacrificed at 3 months of age, they appeared healthy and displayed no obvious motor phenotype.

No Data

No data.

No Data

No data.