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.
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.
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 V.
Age-dependent memory deficits, motor phenotype, and reduced anxiety.
Poly(GA)- and ubiquitin-positive inclusions in neurons are primarily cytoplasmic and also co-localize with HR23A and HR23B proteins and the nuclear pore complex proteins RanGAP1 and Pom121. Neuron loss and astrogliosis in cortex and hippocampus.
Motor deficits, impaired coordination, hyperactivity, increased anxiety, and deficits in contextual and cued fear conditioning.
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.
Yes
C57BL/6J
Tg(Prnp-ITM2B*)6Jckr and Tg(Prnp-ITM2B*)7Jckr
Adult mice fail to gain weight with age. Alopecia. Kyphosis.
Transgenic AD-BXD mice develop amyloid plaques by 6 months of age, although the extent of plaque deposition is strain-dependent.
Transgenic AD-BXD mice exhibit cognitive deficits, assessed using contextual fear conditioning. The age of onset and severity of impairment are strain-dependent.
Yes
C57BL/6J X BXD[strain number]
(B6.Cg-Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax x BXD[strain number]
Individual AD-BXD strains are available as F1 hybrids from The Jackson Laboratory (each strain has its own stock number).
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.
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.
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.
On a standard diet, homozygous mice have normal cholesterol and triglyceride levels, but are more susceptible than wild-type animals to diet-induced atherosclerosis.
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.
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.
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.
Yes
C57BL/6
B6.Cg-Tg(Thy1-APP)3Somm/J
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.
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.
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.
Yes
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.
Viable and fertile. 6 month-old animals develop decreases in body weight, and a spinal deformity (kyphosis) is common. Impaired neurogenesis.
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.
No
C57BL/6 x DBA/2
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
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.
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.
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.
Yes
C57BL/6
Apptm2.1Tcs/Apptm2.1Tcs
No overexpression of APP. Generates wild-type levels of AICD.
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.
Yes
C57BL/6
Apptm3.1Tcs/Apptm3.1Tcs
No overexpression of APP. Wild-type levels of AICD.
Amyloid plaques, plaque-associated neuritic dystrophy, and neuroinflammation, similar to AppNL-G-F.
Deficits in the Y-maze test of working memory, similar to AppNL-G-F.
Yes
C57BL/6J
Compared with AppNL-G-F mice, AppNL-G-F/MAPT double knock-in mice showed accelerated propagation of pathological tau species after AD-derived tau was injected into the mouse brain.
Available through Takaomi Saido, RIKEN Center for Brain Science.
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.
Yes
C57BL/6J
B6.Cg-Tg(Thy1-APPSw,Thy1-PSEN1*L166P)21Jckr
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.
Tau accumulations, dystrophic neurites, astrocytosis, neuronal loss, and synapse loss were more pronounced adjacent to cortical plaques. Tangles were not observed.
Homozygotes: Amyloid plaques and plaque-associated microgliosis from 4 months of age; cerebral amyloid angiopathy and dystrophic neurites from 8 months of age. Heterozygotes: Amyloid plaques at 16 months of age.
Unknown.
Yes
C57BL/6J
B6(Cg)-Apptm1.1Dnli/J
Increased levels of CSF total tau and neurofilament light chain in AppSAA homozygous mice at 8 months of age. Significant alterations of the transcriptomes and lipidomes in microglia of AppSAA homozygotes.
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.
Yes
APPsw mice on C57BL/6; Pdgfrβ+/- mice on 129S1/SvlmJ.
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.
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.
Yes
C57BL/6J; C57BL/6N
B6.Cg-Nos2tm1Lau Tg(Thy1-APPSwDutIowa)BWevn/Mmjax
Decreased neuropeptide Y staining throughout the hippocampus, particularly in the CA3 region and subiculum.
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.
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.
Yes
(129X1/SvJ x 129S1/Sv)F1-Kitl<+>
B6.129-Tg(APPSw)40Btla/Mmjax
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.
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.
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.
Yes
Line C3-3: C57BL/6J; Line S-9: hybrid strain C3H/HeJ;C57BL/6J) backcrossed to C57BL/6J
B6.Cg-Tg(APP695)3Dbo Tg(PSEN1dE9)S9Dbo/J
At 19 months, small but significant decrease in acetylcholinesterase activity in the hippocampus and choline acetyl transferase (ChAT) in the hippocampus and cortex.
Amyloid plaques begin to emerge in the cortex at about 4 months of age and in the hippocampus at about 6 months. Gliosis and dystrophic neurites are associated with plaques. Amyloid angiopathy has been observed in the retina.
Hyperactivity is apparent by 6 months. Deficits in the Morris water maze emerge between 6 and 10 months and worsen with age.
Yes
C57BL/6J
B6.Cg-Tg(APPswe,PSEN1dE9)85Dbo/Mmjax
A substantial proportion of APPswe/PSEN1dE9 mice exhibit electrographic and behavioral seizures.
Available from the Jackson Laboratory, JAX MMRRC Stock# 034832 (formerly Jackson Lab Stock #005864)
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).
Yes
C57BL/6;C3H
B6C3-Tg(APPswe,PSEN1dE9)85Dbo/Mmjax
Kinked tail phenotype that is believed to be due to genetic background.
The Jackson Lab; available through the JAX MMRRC Stock# 034829 (formerly Jackson Lab Stock # 004462); Live
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.
No
Origin: C57BL/6 x DBA/2
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.
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.
Yes
Origin:C57BL/6 x CBA; chimeric mice breed to CD-1 mice
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.
Yes
Originally generated on FVB/N background; available at reMYND as C57BL/6xFVB/N
Tg(Thy1-APPLon)2Vln/0
Increased mortality (72% by day 180). Increased incidence of seizures.
Available through the KU Leuven Research and Development Office; the CRO reMYND offers research services with this line.
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.
Yes
Originally generated on FVB/N background; available at reMYND as C57BL/6xFVB/N
Tg(Thy1-APPLon)2Vln/0; Tg(Thy1-PSEN1*A246E)2Vln/0
The CRO reMYND offers research services with this line.
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.
Yes
Inbred C57BL/6
Premature lethality. Trend toward hyperactivity. Reduced calbindin and Fos levels in the dentate gyrus.
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.
Yes
Origin: B6D2 F1
Deficits in synaptic plasticity, LTP, and functional connectivity as measured by resting-state fMRI.
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.
Yes
Co-injection of transgenes into B6CBF1 oocytes, back-crossed to C57BL/6
B6;CB-Tg(Thy1-PSEN1*M146V/Thy1-APP*swe)10Arte
Good breeding capabilities and no premature death.
Amyloid plaques, reactive astrocytes and microglia, and dystrophic neurites accumulate up to day 120, but to a lesser degree than in control 5xFAD (5xFAD mice homozygous for a floxed Bace1 gene), then recede thereafter.
Normal contextual and cued fear conditioning, tested at 8 to 10 months of age.
Yes
C57BL/6J
Deficit in long-term potentiation at Schaffer collateral–CA1 synapses in slices from 10- to 12-month-old mice, but less severe than that seen in slices from control mice (5xFAD mice homozygous for a floxed Bace1 gene).
Normal learning and memory in the Morris water maze, normal alternation in the Y-maze test of working memory, and normal cued and contextual fear conditioning; possible hyperactivity in novel situations.
Delayed learning, but normal memory, in the Morris water maze; normal alternation in the Y-maze test of working memory, normal cued and contextual fear conditioning. Hyperactivity in when placed in novel environments.
Yes
C57BL6
Spontaneous behavioral seizures and epileptiform discharges in EEGs.
None observed: hippocampal mossy fiber organization and sciatic-nerve myelination were normal.
Performed similarly to controls in a battery of tests (Y-maze, contextual fear conditioning, pre-pulse inhibition, open field, and light-dark transition task).
Yes
C57BL/6N
C57BL/6-Bace1tm1.1mrl
Deficit in long-term potentiation at Schaffer collateral–CA1 synapses.
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.
No
C57BL/6J
B6.129-Bace1tm1Pcw/J
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).
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.
Yes
B6C3, backcrossed to C57BL/6J to generate congenic strain
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.
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.
Intranuclear foci containing antisense and antisense repeat RNA; cytoplasmic inclusions containing sense and antisense dipeptide repeat proteins; accumulation of phosphorylated TDP-43 and stress granule-associated proteins; neuron loss and gliosis.
Motor and cognitive deficits emerge between 3 and 6 months of age. Hyperactivity seen by 3 months.
Yes
C57BL/6J
Mislocalization of RanGAP1 suggests nucleocytoplasmic transport defects.
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.
Neuron loss in the frontal cortex, beginning between 3 and 6 months of age. Microgliosis and astrogliosis evident at 6 and 9 months, respectively. No TDP-43 inclusions seen in mice studied up to 8 months of age. DNA damage and mitochondrial abnormalities observed.
Deficits in social behavior and increased anxiety emerge between 3 and 6 months. Working memory is intact at least through 9 months of age.
Yes
C57BL/6
Morphological defects in mitochondria seen in mice as young as 3 months of age. Disease-related phenotypes were prevented or reversed by reducing levels of poly(GR) in adult mice.
Amyloid plaques, plaque-associated gliosis, cerebral amyloid angiopathy; possible neuron loss in hippocampal area CA1.
Transgenic mice are hyperactive. Working memory (spontaneous alternation in the Y-maze) is normal at 7 to 8 months, but short-term memory (tested in the Y-maze) is impaired in males (data from females is not available, as wild-type females are unable to perform this test).
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.
No
C57BL6/129
fPS1/fPS1Δ;Nestin-Cre (PS1 cKO)
Mice are small. Premature death at 2-3 months of age.
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.
Yes
C57BL/6J
B6(C3H)-Sod1m1H/J
Liver tumors, kyphosis (hunched back), reduced body weight, loss of SOD1 activity.
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.
Progressive (not developmental) loss of lumbar spinal motor neurons, starting by 12 months of age; partial denervation of hindlimb muscles. Mislocalization of mutant FUS from nucleus to cytoplasm.
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.
Yes
Transgene injected into B6SJL oocytes. Maintained on C57BL/6, therefore subsequent generations have a higher percentage of C57BL/6.
B6;SJL-Tg(Prnp-FUS*R521C)3313Ejh/J
Growth retardation, muscle atrophy, DNA damage, and RNA splicing defects. Males may be sterile.
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
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.
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.
Yes
C57Bl/6/SJL founder mice backcrossed to C57Bl/6
Tg (Prnp-FUS)WT3Cshw/J
Born at Mendelian ratios. Focal muscle atrophy and signs of denervation in hindlimb muscles. Most founder lines did not propagate the transgene.
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.
Yes
C57Bl/6
Denervation and atrophy of the gastrocnemius muscle in the hindlimb.
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).
Yes
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 .
B6.Cg-Mapttm1(EGFP)Klt Tg(MAPT)8cPdav/J
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).
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.
Yes
C59Bl/6J
C57BL/6-Tg(tetO-MAPT*A152T)L1Lms/J
Increase in basal synaptic activity and epileptiform spikes. Life span normal.
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.
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.
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.
Yes
Transgene injected into fertilized eggs from C57BL/6J x C3HeJ.
B6;C3-Tg(tetO-TARDBP*)4Vle/J
Downregulation of endogenous mouse TDP-43. No change in mortality up to 7 months of age. Mendelian ratios of offspring.
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.
Yes
C57BL/6
B6.Cg-Zbtb20Tg(PDGFB-APPSwInd)20Lms/2Mmjax
On the C57BL/6J background hippocampal hyperexcitability was observed and cortical and hippocampal spontaneous nonconvulsive seizures.
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.
Yes
C57BL/6, DBA/2, SW Mixed Background
Tg(Prnp-MAPT*P301L)JNPL3Hlmc
Eye irritiation, possibily due to carrying the Pde6brd1 retinal degeneration mutation
carries Pde6brd1 mutation
Levels of phospho-substrates of LRRK2 (e.g., Rab10) are increased in the brain. Endocytosis and axonal transport defects in neurons. Cholinergic innervation density is lower in the prelimbic/infralimbic cortical areas and dorsomedial striatum, but not in the dorsal lateral geniculate nucleus in 2-6-month-old males. Microglial immunostaining is similar in the striatum and midbrain at 8 weeks
Attention deficits, slower information processing speeds, and impaired goal-directed learning are evident in 2-6-month-old mice—deficits rescued by systemic administration of the acetylcholinesterase inhibitor donepezil. Cognitive flexibility and novel objective recognition similar to controls. Sleep behavior is perturbed at 8-10 months of age.
Yes
C57BL/6NTac
C57BL/6-Lrrk2tm4.1Arte
Functional and structural synaptic alterations and impaired synaptic plasticity observed during development (P21) in the dorsal striatum and NAc, some of which may be transient. Impaired synaptic plasticity (LTP) in striatum present early (P21) and persists into adulthood.
Brain appears normal. No neuronal or cell death at 12 months. Impaired neurite motility and synaptic vesicle endocytosis in cultured neurons. No increase in α-synuclein or ubiquitin levels or aggregation; however, cultured neurons developed more inclusions when exposed to exogenous α-synuclein fibrils. Decreased striatal dopamine content, decreased evoked release.
Apparently normal behavior. No change in activity level or motor coordination at 12 months. Motor deficits appear at 18 months.
Yes
A BAC construct was injected into B6C3 F1 oocytes. Founder line 2 was established and maintained by breeding to C57BL/6J inbred mice.
B6.Cg-Tg(Lrrk2*G2019S)2Yue/J
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. Synaptic vesicle endocytosis impaired in cultured ventral midbrain neurons. Tg mice spend less time in the REM sleep phase.
Age-dependent dopaminergic neuron degeneration in the substantia nigra, though reports are mixed. No reduction in striatal dopaminergic terminals or dopamine levels. Some reports of α-synuclein accumulation. Abnormal mitochondria in striatal neurons and microglia; accumulation of autophagic vacuoles. Evidence for activated striatal microglia and increased levels of CD68 and TNF-α in whole brain.
Deterioration of Rotarod performance in 14- to 18-month-old mice. Muscle weakness observed on the hanging wire test by 8 months of age. No change in pre-pulse inhibition of the acoustic startle reflex. Anxiety/depression-like symptoms at 10-12 months.
Yes
Transgene introduced into C57BL/6J x C3H/HeJ embryos. Founder mice were bred with C57BL/6J mice.
B6;C3-Tg(PDGFB-LRRK2*G2019S)340Djmo/J
No differences in body weight or survival. Reduced serotonin levels in the hippocampus at 10-12 months. Age-dependent increase in 5-HT1a receptors in the hippocampus, amygdala, and dorsal raphe nucleus.
No loss of dopaminergic (TH+) neurons in the substantia nigra pars compacta at 12 and 22 months. No loss of TH-immunoreactive neurons in the locus coeruleus. Basal levels of striatal dopamine, DOPAC, and HVA were comparable between KI and wild-type mice at 3, 12, and 23 months. However, evoked dopamine release in the striatum was reduced in adult heterozygous KI mice.
Acoustic startle reflex equal to wild-type mice at 12 months of age. Motor learning impaired upon antagonism of dopamine receptors (D1 and D2).
Yes
The mutant colony was established in B6/129 F1 mice, but backcrossed to C57BL/6J wild-type mice for at least 12 generations.
B6.Cg-Lrrk2tm1.1Shn/J
Intracellular protein transport impaired. PKA activity is elevated in the striatum. Ciliation in striatal cholinergic neurons is decreased and primary cilia formation is perturbed in the somatosensory cortex.
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.
Yes
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.
STOCK Gt(ROSA)26Sortm1(LRRK2*R1441C)Djmo/J
Fertile. Normal survival. No overt olfactory deficits.
No evidence of increased neuroinflammation, neuronal death, or brain atrophy in MAPT knock-in mice, compared with wild-type mice.
MAPT knock-in mice perform similarly to wild-type mice in the Y-maze test of working memory.
Yes
C57BL/6J
Compared with wild-type mice, MAPT knock-in mice showed accelerated propagation of pathological tau species after AD-derived tau was injected into the mouse brain.
Available through Takaomi Saido, RIKEN Center for Brain Science.
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.
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.
Yes
C57BL/6 x DBA
mThy1-hAβPP751 Swe Lon
Available through Eliezer Masliah. The CRO PsychoGenics offers research services with this line.
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.
Yes
NEFH-tTA mice and tetO-hTDP-43ΔNLS line 4 mice were maintained on a mixed C57BL/6J x C3HeJ background.
B6;C3-Tg(NEFH-tTA)8Vle Tg(tetO-TARDBP*)4Vle/J
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).
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.
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.
Human ApoE3 protected against the age-dependent neurodegeneration seen in APOE -/- mice.
Unknown.
No
Origin: C57BL/6J; backcrossed with murine APOE-null mice
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).
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.
No
Origin: C57BL/6J; backcrossed with murine ApoE-null mice
Neuronal ApoE expression was widespread in the brain. Expression of ApoE4 did not protect against kainic acid-induced neuronal damage.
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.
No
C57BL/6× DBA/2
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.
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.
Yes
The BAC was microinjected into fertilized FVB/NJ zygotes, then bred to FVB/NJ inbred mice.
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.
Yes
C57B6 x DBA2
Alterations in sleep/wake states, thermoregulation, and motor activity.
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.
No
C57BL/6
Deficits in synaptic transmission at 2-4 months, prior to amyloid deposition.
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.
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). Increase in factors involved in toll-like receptor signaling in the cerebellum, and increased astrocytic and microglial markers in the corticospinal tract and striatum.
Reduced spontaneous locomotor activity in open-field test. No difference in strength or coordination.
Yes
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.
B6;129-Pink1tm1Aub/J
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 spikes. Subtle alterations in gene expression in cerebellum, midbrain, and striatum.
Normal numbers of dopaminergic neurons and tyrosine hydroxylase levels in substantia nigra at 8-9 months of age. Alterations in the dendrites of midbrain dopaminergic neurons and cultured cortical neurons. Altered shape, density, and movement of dendritic mitochondria in cultured primary neurons from embryonic mice. Reduced BDNF levels in the midbrain and cortex at 10 months.
Reduced spontaneous locomotor activity and skill at 3-6 months. Modest vocalization deficits at 4-6 months.
Yes
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.
B6.129S4-Pink1tm1Shn/J
Heavier than wildtype mice at 5 months. Plasticity abnormalities: reduced LTP and absent LTD in response to high frequency stimulation; reversed by dopamine agonists. Abnormal rise in serum cytokines in response to exhaustive exercise which acutely stresses mitochondria. Cardiac hypertrophy observed at 2 and 6 months of age.
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.
Yes
C57BL6
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.
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.
Yes
C57BL/6J, for at least six generations
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.
Alzheimer's Disease, Dementia with Lewy Bodies, Frontotemporal Dementia
Hypertrophic astrocytes in the hippocampi, revealed by GFAP immunohistochemistry. Microglial activation revealed by TSPO PET imaging.
Unknown.
Yes
C57BL/6J
Plcg2em1Bwef
A subset of DAM genes and genes related to Plcγ2 signaling, the neuronal cytoskeleton, and myelination are differentially expressed in the brains of knock-in mice, compared with wild-type animals.
Plaque burdens in the cortex and subiculum were elevated in 5xFADM28L mice but microglia showed less interaction with plaques, compared with 5xFAD.
Six-month-old 5xFADM28L and 5xFAD mice showed similar deficits in working memory, assessed in the Y-maze.
Yes
C57BL/6J
Impaired synaptic function—including deficits in basal synaptic transmission and long-term potentiation—similar to 5xFAD. Differences in microglial gene expression, compared with 5xFAD.
Microglia in Plcg2*P522R mice are more abundant, simpler in shape, and have lower levels of the PLCγ2 substrate, PIP2, than microglia in wild-type mice. Sight decrease in number of dendritic spines in hippocampal CA1 of Plcg2*P522R mice, compared with wild-type mice.
Sex- and region-dependent increases in plaque burden, and decreases in microglia-plaque interactions, in Plcg2*P552R x APPNL-G-F mice, compared with APPNL-G-F.
Unknown.
Yes
C57BL/6
B6.Cg-Plcg2em1Msasn/J x Apptm3.1Tcs/Apptm3.1Tcs
The PLCγ2 P522R variant protected against synapse loss in APPNL-G-F mice.
Cytoplasmic mislocalization of human FUS, but no cytoplasmic inclusions or signs of neuronal loss.
No overt behavioral abnormalities.
Yes
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.
B6.Cg-Tg(Prnp-FUS*R495X)78Ljh/J
By 8-12 months, EMG detected hindlimb muscular abnormalities including fibrillation potentials, muscle denervation, and a reduction in the number of motor units.
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.
Yes
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.
B6.Cg-Tg(Prnp-FUS)17Ljh/J
Unexplained premature lethality about 203 days of age, proceeded by less than a week of ill-health.
Brain atrophy by 9 months of age. Increased microgliosis, astrogliosis and synapse loss, compared with PS19 mice carrying TREM2 with the R47H mutation.
Not known.
Yes
C57BL/6
Increased expression of pro-inflammatory cytokines and DAM (disease-associated microglia) genes, compared with PS19 mice carrying TREM2 with the R47H mutation.
Decreased brain atrophy, microgliosis, astrogliosis, and synapse loss, compared with PS19 mice carrying the common variant of TREM2.
Not known.
Yes
C57BL/6
Decreased expression of pro-inflammatory cytokines and DAM (disease-associated microglia) genes, compared with PS19 mice carrying the common variant of TREM2.
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.
No
FVB/N
Tg(Thy1-PSEN1*A246E)2Vln/0
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.
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.
Yes
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.
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.
No
B6/D2/Swe/SJL mixed background
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.
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.
Yes
C57BL/6
Tg(Thy1-APPSwe,Prnp-PSEN2*N141I)152HLaoz
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).
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.
Yes
C57BL/6, DLB/2, crossed to C57BL/6
Tg(Thy1-APPSwe)71Jgr x Tg(Prnp-PSEN2*N141I)30Jgr
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.
Originally generated in a B6.D2 background, then crossed into C57BL/6J.
Tg(Prnp-PSEN2*N141I)30Jgr
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.
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.
Yes
B6/D2/Swe/SJL mixed background
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.
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.
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.
No
Origin: 129P2/OlaHsd; backcrossed to C57BL/6
B6;129P-Psen1tm1Vln/J
When crossed with Cre recombinase driven by Thy1, LTP induction is slightly altered.
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.
No
C57BL/6
B6.129-Psen1tm1Mpm/J
Mice are viable, fertile, and normal in size. No gross physical or behavioral abnormalities.
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.
Yes
129S6FVB F1
Reduced body weight at 24-27 months relative to non-Tg littermates and those expressing only tTA.
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.
Yes
4510 mice are on an FVB background. Neuropsin-tTA mice are on a C57BL/6 background.
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.
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.
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. It should be noted that disruption of an endogenous mouse gene, caused by random insertion of the MAPT transgene, significantly contributes to the neuropathological and neurodegenerative phenotypes observed in rTg4510 mice
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.
No
C57BL6 x C3H, maintained in B6C3 background
Altered microtubule binding and slow axonal transport of tau. Reduced lifespan.
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.
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.
Yes
C57BL/6J x C3H/HeJ)F2
Elevated dismutase activity in the brain and spinal cord (~7-fold).
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.
Yes
Transgene injected into hybrid (C57BL/6J x C3H/HeJ)F2 embryos.
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.
Yes
C57Bl/6/SJL.
B6SJL-Tg(G93A-SOD1)1Gur/J
Weight loss. The mutant SOD1 retains enzymatic activity.
Mice do not generate amyloid plaques. Disrupted nigrostriatal connectivity and thinner inner nuclear layer of the retina.
Hyperactivity and reduced anxiety, compared with wild-type mice.
Yes
Generated on a mixed 129SvEmcTer X C57BL/6N genetic background, subsequently backcrossed to C57BL/6J.
Deficits in salt homeostasis, lowered mean arterial blood pressure, decreased fat, and increased lean body mass. Increased neuronal ERK signaling and enhanced adult neurogenesis.
Progressively loss of dopaminergic neurons in the substantia nigra pars compacta, observed by 8.5 months. 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.
Yes
Transgene injected into C57/BL6 oocytes, then bred to C57/BL6J.
No overt neuronal loss. Alterations in dopaminergic-associated proteins in the striatum, substantia nigra, and nucleus accumbens. 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. At 11–12 months, spatial memory impaired as assessed by the Barnes circular maze.
Yes
Established as C3H/HeJ x C57BL6/J hybrids, then maintained by backcrossing to C57Bl6/J.
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.
Yes
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.
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.
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.
Yes
Inbred 129/SvEvTac background.
Microglial abnormalities. Reduced cardiolipin content in the brain. Some mitochondrial abnormalities.
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.
Yes
C57BL/6J x CBA mice backcrossed to C57BL/6J.
B6.Cg-Tg(Prnp-TARDBP*A315T)95Balo/J
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.
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.
Yes
The Prp-TDP43A315T transgene was introduced into oocytes from C57BL/6J x CBA mice.
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
At 18 months of age, p62- and ubiquitin-positive inclusions in the ventral regions of the spinal cord, although apparently not in the cytoplasm of motor neurons. TDP-43 normally localized to the nucleus in 12-month mice. At 24 months, a 28 percent reduction in the number of motor neurons in the sciatic motor neuron pool, compared with control littermates.
Grip strength in both male and female mice begins to decline at 12 months of age.
Yes
DBA/2J x C57BL/6J
Tardbp M323K
By 24 months, there is a nearly 40 percent reduction in force measured in tibialis anterior muscles and a 15 percent reduction in motor units innervating the extensor digitorum muscle.
Mice from original founders, on a hybrid DBA/2J x C57BL/6J background, are available from the RIKEN BioResource Center, BRC# GD000110.
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.
Yes
Transgene injected into C57BL/6 x C3H oocytes, some backcrossing to C57BL/6
No differences in body temperature, locomotor activity, or Rotarod performance, relative to non-Tg controls.
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.
Yes
TAS10 transgene originally injected into C57BL/6 x C3H oocytes, with some backcrossing to C57BL/6. TPM generated on pure C57BL/6 background.
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.
Yes
C57BL/6 (75%) and 129/Ola (25%).
Muscle fibers in the quadriceps and latissimus muscles appeared to be degenerative/regenerative. Progressive spine curvature.
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.
Yes
C57BL/6J
B6.Cg-Tg(Thy-MAPT*)2652Gds
Homozygous mice have reduced body weight, reduced fertility, and premature death. Some homozygous mice also exhibit seizure activity.
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.
Yes
B6C3F1 embryos, backcrossed to C57BL/6
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
Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy
Neuron loss and astrogliosis were observed in the cortices of 3-month-old mice.
Compared with GFP-AAV controls, TauA152T-AAV mice showed deficits in contextual and cued fear conditioning, increased hyperactivity, and decreased rearing in the open-field test, and spent more time in the open arms of the elevated plus maze. TauA152T-AAV mice also exhibited motor impairment on the Rotarod.
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.
Age-dependent deterioration of sensorimotor functions, including coordination deficits on the Rotarod and a decrease in muscle strength. No deficits in learning or memory.
No
Mixed background (BALB/c x C57B1/B6 x B6D2F1)
Humanized splicing pattern of murine tau, leading to the production of 3R tau rather than 4R tau. No anxiety phenotype.
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.
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.
Yes
FVB/N
Thy1-hTau.P301L
Premature death around 8-12 months, preceded by weight loss, hyperkyphosis, reduced activity, and upper airway dysfunction.
The CRO reMYND offers research services with this line.
Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy
Neurofibrillary tangles and gliosis, but no cortical neuron loss, at 6 months of age.
Hyperactivity in the open field, decreased time spent in the center of open field, more time spent in the open arms of the elevated plus maze, and deficits in cued and contextual fear conditioning at 6 months of age.
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.
Yes
(C57BL/6 x C3H)F1
B6;C3-Tg(Prnp-MAPT*P301S)PS19Vle/J
Clasping and limb retraction when lifted by the tail at three months, followed by limb weakness and brain atrophy. Homozygous females do not mate.
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.
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.
Yes
B6SJL/F1; backcrossed to C57BL/6J
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.
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.
Yes
C57BL/6
Missorting of tau into the somato-dendritic compartment. Calcium dysregulation at synaptic boutons. Deficits in synaptic plasticity, including LTP and LTD.
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.
Yes
B6SJL/F1
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.
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.
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.
Yes
Transgene injected into C3H x C57Bl/6 embryos and then crossed with C57Bl/6.
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.
Yes
Transgene injected into fertilized hybrid B6SJLF1oocytes. Founders bred with CD1 to create hybrid CD1 and B6SJLF.
STOCK Tg(Prnp-TARDBP*A315T)23Jlel/J
Prior to motor deficits, mice exhibit increased fat storage, decreased lean muscle mass, and larger adipocytes in white fat.
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.
Yes
Transgene injected into C3H x C57Bl/6 embryos. Founders backcrossed with C57Bl/6.
Impaired recovery after crush injury to the sciatic nerve (e.g., delayed recovery of motility and reduced axon regrowth). Normal lifespan and fertility.
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.
Yes
Transgene injected into fertilized C57BL/6 oocytes. Founders bred with B6.
C57BL/6-Tg(Prnp-TARDBP*M337V)4Ptrc/J
Reduced brain and body weight compared with non-Tg littermates.
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.
Yes
Transgene injected into BL6/SJL oocytes. Founders crossed to C57BL6/J.
Postnatal growth retardation and weight loss. Transgene induced downregulation in endogenous TDP-43. Increased caspase-3 expression. Ultrastructural mitochondria abnormalities.
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.
Yes
Transgene introduced into C57Bl6/C3H oocytes. Founders crossed to C57/Bl6 for a minimum of four generations.
No TDP-43- or tau-positive inclusions. No apparent loss of upper or lower motor neurons, but 25% decrease in number of parvalbumin-positive neurons in frontal cortex.
Attention deficits in a five-choice serial reaction time task, memory deficits in a novel-object-recognition task, deficits in a marble-burying task. No apparent motor impairments.
Yes
C57Bl/6J
Gene-expression and splicing differences, compared with wild-type mice, including upregulation of Tardp, and altered splicing of Tardp, Sort1, Mapt.
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.
Yes
Transgene injected into B6SJLF1 oocytes. Founders crossed with CD1 mice.
B6SJL-Tg(Prnp-TARDBP)4Jlel/J
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
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.
Yes
Transgene injected into C3H x C57Bl/6 embryos. Founders crossed with C57Bl/6.
Impaired recovery following crush injury to the sciatic nerve (e.g., delayed recovery of motility, reduced axon regrowth). Normal lifespan and fertility.
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.
Yes
Transgene introduced into BL6/SJL oocytes. Founders crossed to C57BL6/J.
B6;SJL-Tg(Thy1-TARDBP)4Singh/J
Elevated anxiety at a young age. Size and weight of homozygotes lag behind non-Tg and hemizygous littermates.
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.
Yes
Transgene injected into fertilized C57BL/6 oocytes. Founders bred with B6.
C57BL/6-Tg(Prnp-TARDBP)3cPtrc/J
Early reductions in body and brain weight in homozygous mice. Reduced dendritic spines in the hippocampus and lower mRNA levels of synaptic markers.
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.
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.
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.
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.
Yes
B6;SJL Mixed Background
B6;SJL-Tg(APPSWE)2576Kha
Between 7 -12 weeks males become aggressive and begin to fight. Premature mortality: mortality of >20% anticipated, particularly in males.
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.
Yes
C57BL/6, DBA/2, SJL, SW Mixed Background
Tg(APPSWE)2576Kha; Tg(Prnp-MAPT*P301L)JNPL3Hlmc
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.
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.
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.
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).
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.
Yes
C57BL/6J
Tg-ArcSwe have reduced body weight compared with nontransgenic littermates.
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.
Yes
Hybrid C3H/He-C57BL/6
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
Intracellular Aβ immunoreactivity in the hippocampus and cortex, beginning by 12 months. No amyloid plaques, hyperphosphorylated tau, microgliosis, astrogliosis, or neuron loss through 24 months.
Learning deficits, as well as indicators of increased anxiety and depression, by 7 months.
Yes
C57BL/6N
More rapid decay of hippocampal long-term potentiation, compared with wild-type mice. Age-dependent cholinergic loss in hippocampus; lower rates of serotonin turnover in hippocampus, ventral striatum, and amygdala.
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.
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.
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.
Available through Eliezer Masliah, Robert Rissman for academic research; others please contact the Office of Innovation and Commercialization at the University of California, San Diego. The CRO Scantox Neuro offers research services with this model.
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.
Yes
C57BL6/CBA; backcrossed to C57BL6
Fertile with normal frequency and size of litters. Stably transmits the transgene to offspring. Deficits in hippocampal synaptic transmission.
Amyloid plaques with plaque-associated microgliosis. Reduced plaque burden, altered microglial and plaque morphology, and less severe plaque-associated neuritic dystrophy, compared with 5xFAD.
5xFAD/TREM2 mice perform comparably to wild-type mice in a contextual fear conditioning test, while 5xFAD mice are impaired.
Lower density of activated microglia surrounding amyloid plaques in 5XFAD mice expressing the R47H variant of human TREM2 compared with those expressing the common variant.
No data.
Yes
C57BL/6 X CBA, back-crossed for at least 4 generations to C57BL/6
Microglial number remains constant and microglial size decreases with age in the corpus callosum of Trem2 KO mice, while microglial number increases and microglial size remains stable in wild-type mice.
No cognitive/behaviorial deficits observed.
Yes
C57BL/6
C57BL/6 -TREM2tm1cln
Osteopenic. Impaired microglial response to experimental demyelination, middle cerebral artery occlusion, and facial nerve axotomy.
Compared with 5XFAD, mice deficient in TREM2 show an age- dependent increase in amyloid accumulation in the hippocampus, more severe plaque-associated neuritic dystrophy, and exaggerated neuron loss in the cortex. Microglial containment of plaques is compromised in TREM2-deficient animals. Microglia accumulate autophagosomes.
At six months, mice perform normally in the open-field test, elevated plus maze, three-chamber social-interaction test, and contextual and cued fear-conditioning test.
Yes
C57BL/6N
Trem2tm1(KOMP)Vlcg
Trem2−/− microglia show a muted response to excitotoxicity in vivo, and decreased proliferation and increased apoptosis in vitro. Overexpression of Treml1 is driven by an ectopic Ubiquitin C promoter in the selection cassette.
Reduced plaque burden at early stages of plaque deposition but increased plaque burden at later stages, fewer plaque-associated myeloid cells and astrocytes, less phospho-tau in plaque-associated dystrophic neurites, compared with APPPS1.
Tau phosphorylation and aggregation in the cortex are enhanced in htau mice lacking TREM2, but reactive microglia are smaller and their processes have fewer branches.
No neuron loss, amyloid plaques, or neurofibrillary tangles were observed in mice up to 24 months of age.
Locomotor activity, motor coordination, and working memory similar to wild-type at 2 and 12 months of age.
Yes
C57BL/6J
C57BL/6J-Trem2em1Adiuj/J
Compared with wild-type mice: age-, sex-, and region-dependent differences in glucose uptake and cerebral blood flow; increased mortality of females at 24 months of age; downregulation of genes related to immune function, and degradation of biological material in aged mice.
Reduction in the number and burden of fibrillar amyloid plaques in the hippocampus, fewer plaque-associated myeloid cells, and worse plaque-associated neuritic dystrophy, compared with APPPS1-21 mice homozygous for wild-type Trem2.
Unknown.
Yes
C57BL6/J
Levels of Trem2 transcripts were reduced in APPPS1-21;Trem2+/R47H compared with APPPS1-21;Trem2+/+ and were similar to those in APPPS1-21 mice haploinsufficient for Trem2.
No neuron loss, amyloid plaques, neurofibrillary tangles, vascular leakage, myelin loss, or reactive microglia in mice up to 24 months of age.
Age-related changes in locomotor activity, motor coordination, and working memory, but no genotype-dependent differences through 24 months of age, compared with wild-type mice.
Yes
C57BL/6J
B6(SJL)-Apoetm1.1(APOE*4)Adiuj Trem2em1Adiuj/J
Age-, sex-, and region-dependent differences in glucose uptake and cerebral blood flow, compared with wild-type mice. Increased mortality at 24 months of age. Down-regulation of genes related to immune function and degradation of biological material in aged mice.
Changes in microglial morphology at 4 months but not 12 months, compared with wild-type.
Unknown.
Yes
C57BL/6J
B6(SJL)-Trem2em1Aduci/J
Age-dependent synaptic deficits and age-dependent differences in gene expression, compared with wild-type mice. When crossed with 5xFAD mice, blunted inflammatory responses at 4 months, but exaggerated responses at 12 months.
Age-related microglial activation seen in wild-type mice is absent in homozygotes.
No data.
Yes
Mixed DBA/2J, FVB/ N, C57BL/6J
Trem2em1Bwef
Reduced cerebral blood flow and reduced cerebral glucose metabolism in homozygotes. Bone marrow-derived macrophages from heterozygous and homozygous Trem2 T66M mice show reduced proliferation, survival, and phagocytosis.
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.
No
DBA/2J
B6EiC3Sn a/A-Ts(1716)65Dn/J
Females are smaller, and produce fewer, smaller litters. Males are effectively sterile with hypospermia.
Amyloid plaques, plaque-associated gliosis, cerebral amyloid angiopathy; possible neuron loss in cortex and hippocampal area CA1 in females.
Transgenic mice are hyperactive. Working memory (spontaneous alternation in the Y-maze) is normal at 7 to 8 months, but short-term memory (tested in the Y-maze) is impaired in females (data from males is not available, as wild-type males are unable to perform this test).