Research Models
Alzheimer's Disease
There is a large ongoing effort to characterize animal models of AD in order to better understand disease pathophysiology as well as to identify models suitable for investigating potential therapeutics. By organizing information about the characterization of selected AD models, this resource conveys what is known about each one and facilitates comparison between them.
127 Models
73 Visualizations
Phenotypes Examined
- Neuronal Loss
- Plaques
- Tangles
- Gliosis
- Changes in LTP/LTD
- Cognitive Impairment
- Synaptic Loss
When visualized, these phenotypes will distributed over a 18 month timeline demarcated at the following intervals: 3mo, 6mo, 9mo, 1yr, 15mo, 18mo+.
3xTg
Observed
-
Plaques at 26
Extracellular Aβ deposits by 6 months in the frontal cortex, predominantly layers 4 and 5 and progress with age (Oddo et al., 2003).
-
Tangles at 52
By 12 months extensive tau immunoreactivity in CA1 neurons of the hippocampus, particularly pyramidal neurons, later in the cortex. No tau pathology at 6 months (Oddo et al., 2003).
-
Gliosis at 30
Increased density of GFAP immunoreactive astrocytes and IBA-1 immunoreactive microglia compared with wild-type mice at 7 months (Caruso et al., 2013). Development of gliosis may occur earlier.
-
Changes in LTP/LTD at 26
By 6 months decreased LTP compared with wild type controls. Impairment in basal synaptic transmission. No change at 1 month of age (Oddo et al., 2003).
-
Cognitive Impairment at 17
Cognitive impairment manifests at 4 months as a deficit in long-term retention and correlates with the accumulation of intraneuronal Aβ in the hippocampus and amygdala, but plaques and tangles are not yet apparent (Billings et al., 2005).
Absent
No Data
-
Neuronal Loss at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP, PSEN1, MAPT | APP KM670/671NL (Swedish), MAPT P301L, PSEN1 M146V | APP: Transgenic; PSEN1: Transgenic; MAPT: Transgenic | Alzheimer's Disease | Age-related, progressive neuropathology including plaques and tangles. Extracellular Aβ deposits by 6 months in frontal cortex, more extensive by 12 months. No tau pathology at 6 months, but evident at 12 months. Synaptic dysfunction, including LTP deficits, prior to plaques and tangles. |
Cognitive impairment by 4 months. Impairments first manifest as a retention/retrieval deficit and not as a learning deficit, and occur prior to plaques and tangles. Deficits in both spatial and contextual based paradigms. Clearance of intraneuronal Aβ by immunotherapy rescues the early cognitive deficits in a hippocampal-dependent task. |
5xFAD
Observed
-
Neuronal Loss at 39
Neuron loss in cortical layer 5 and subiculum.
-
Plaques at 7
Amyloid deposition begins at 1.5 months and reaches high levels especially in subiculum and deep cortical layers. Aβ42 also accumulates intraneuronally in an aggregated form within the soma and neurites starting at 1.5 months (Oakley et al., 2006).
-
Gliosis at 9
Gliosis begins at 2 months (Oakley et al., 2006).
-
Synaptic Loss at 39
Synaptic markers synaptophysin, syntaxin, and PSD-95 decrease with age and are significantly reduced by 9 and 12 months.
-
Changes in LTP/LTD at 26
LTP is normal in young animals, but becomes impaired around 6 months (Kimura et al., 2009); specifically, in hippocampal slices from < 4-month-old mice, I/O curves of fEPSPs were not different from those of wild-type controls, but the I/O responses at Schaffer collateral-CA1 synapses at 6 months were impaired.
-
Cognitive Impairment at 17
Impaired spatial memory in Y-maze test at 4-5 months. Impaired stress-related memory, specifically significantly lower levels of contextual freezing at 6 months. Impaired remote memory stabilization at < 4 months.
Absent
-
Tangles at
Absent.
No Data
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP, PSEN1 | APP KM670/671NL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V | APP: Transgenic; PSEN1: Transgenic | Alzheimer's Disease | Amyloid pathology starting at 2 months, including amyloid plaques. Accumulation of intraneuronal Aβ before amyloid deposition. Gliosis and synapse degeneration. Neuron loss in cortical layer 5 and subiculum. No neurofibrillary tangles. |
Age-dependent memory deficits including spatial memory, stress-related memory, and memory stablization. Motor phenotype and reduced anxiety. |
ADanPP
Observed
-
Plaques at 9
Vascular amyloid deposits and punctate parenchymal aggregates first occur in the hippocampus and increase with age, spreading throughout the brain, including the cortex, amygdala, thalamus, and brainstem in hemizygous mice.
-
Gliosis at 17
Astrogliosis and microgliosis increase with age and increasing ADan-amyloid deposition.
-
Cognitive Impairment at 78
The only ages tested were 6 months and 18-20 months. Mice 18-20 months of age exhibited both motor and spatial learning defects in the Morris water maze, and increased anxiety in the open field test. No impairments were observed in 6 month-old mice.
Absent
-
Neuronal Loss at
Absent.
-
Tangles at
Absent.
No Data
-
Synaptic Loss at
Unknown.
-
Changes in LTP/LTD at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| ITM2B (BRI2) | BRI2: Familial Danish Dementia (FDD) duplication | ITM2B (BRI2): Transgenic | Familial Danish Dementia, Alzheimer's Disease, Cerebral Amyloid Angiopathy | ADan deposition starts in the hippocampus and meningeal vessels at 2 months and increases with age. By 18 months, deposition is widespread. The majority of amyloid deposits are associated with the vasculature, where they destroy the integrity of the vessel wall and lead to microhemorrhages. Parenchymal amyloid plaques surrounded by microglia and dystrophic neurites are also present. |
Impaired performance in Morris water maze, due to a combination of both motor deficits (i.e. reduced swim speed) and spatial learning deficits reported at 18-20 months. Open field test at 18-20 months also showed an anxiety-related phenotype. |
APP23
Observed
-
Neuronal Loss at 61
Neuronal loss (14-28%) has been reported in the CA1 region of the hippocampus in 14-18 month old mice (Calhoun et al., 1998).
-
Plaques at 26
Congophillic, dense-core amyloid plaques first appear at 6 months, and increase in size and number with age. Amyloid plaques can occupy more than 25% of the neocortex and hippocampus in 24 month-old mice (Sturchler-Pierrat et al., 1997; Calhoun et al., 1998).
-
Gliosis at 26
Activated microglia in close proximity to dense amyloid plaques (Stalder et al., 1999). Upregulation of neuroinflammatory markers and activation of astrocytes and macrophages. Age-associated increase in components of the complement system, namely C1q and C3, at later ages (9 and 18 months, respectively) (Reichwald et al., 2009).
-
Cognitive Impairment at 13
Spatial memory defects in Morris Water maze at 3 months and progresses with age (Van dam et al., 2003; Kelly et al., 2003).
Absent
-
Tangles at
Dystrophic neurites containing hyperphopshorylated tau surounds Aβ plaques, but no neurofibrillary tangles are observed (Sturchler-Pierrat et al., 1997).
-
Synaptic Loss at
Neocortical synapses were examined in mice as old as 24 months of age; no evidence of alterations in the number of synapses or levels of synaptophysin were observed (Boncristiano et al., 2005).
-
Changes in LTP/LTD at
LTP in the hippocampus and prefrontal cortex is normal at all ages studied: 3, 6, 9, 12, 18 and 24 months (Roder at al., 2003).
No Data
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP | APP KM670/671NL (Swedish) | APP: Transgenic | Alzheimer's Disease, Cerebral Amyloid Angiopathy | Aβ deposits first observed at 6 months. Congophilic plaques increase in size and number with age and are surrounded by activated microglia, astrocytes, and dystrophic neurites containing hyperphosphorylated tau (although no neurofibrillary tangles). Neuronal loss in the CA1 region of the hippocampus. Mice also develop CAA, and microhemorrages occur at later ages. |
Spatial memory defects in Morris Water maze at 3 months and progresses with age. Memory deficits in passive avoidance were observed in 25 month-old mice, but not at younger ages. |
APP23 x PS1-R278I
Observed
-
Plaques at 26
By 6 months of age amyloid plaques accumulate in the cortex and hippocampus. A high percentage of plaques are thioflavin-S –positive cored plaques.
-
Gliosis at 39
Astrocytosis in the vicinity of plaques in the hippocampus and cortex by 9 months.
-
Cognitive Impairment at 13
Short-term memory deficits are apparent by 3 to 4 months as measured by the Y maze.
Absent
-
Tangles at
Not observed.
No Data
-
Neuronal Loss at
No data.
-
Synaptic Loss at
No data.
-
Changes in LTP/LTD at
No data.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP, PSEN1 | PSEN1 R278I | APP: Transgenic; PSEN1: Knock-In | Alzheimer's Disease | Amyloid deposition by 6 months of age in the cortex and hippocampus. Abundant reactive astrocytes in the vicinity of plaques. Elevated Aβ43 in the brain by 3 months. High density of cored plaques. Pyroglutamate Aβ (N3pE-Aβ) associated with amyloid plaques. |
Short-term memory deficits apparent by 3-4 months as measured by the Y maze. |
APP751SL/PS1 KI
Observed
-
Neuronal Loss at 23
Some cell loss detectable as early as 6 months in female mice. At 10 months extensive neuronal loss (>50%) is present in the CA1/2 hippocampal pyramidal cell layer. SNeuronal loss also occurs in the frontal cortex and cholinergic system (Casas et al., 2004; Christensen et al., 2008; Christensen et al., 2010).
-
Plaques at 11
Aβ deposition at 2.5 months compared to 6 months in APPSL mice. At 6 months, numerous compact Aβ deposits in the cortex, hippocampus, and thalamus, whereas in age-matched APPSL mice only very few deposits restricted mainly to the subiculum and deeper cortical layers. At 10 months, deposits increased in distribution, density, and size in both models (Casas et al., 2004).
-
Gliosis at 11
Astrogliosis occurs in parallel with Aβ deposition, starting around 2.5 months, and in proximity to Aβ-positive neurons (Wirths et al., 2010).
-
Synaptic Loss at 24
At 6 months, levels of pre- and post-synaptic markers are reduced (Breyhan et al., 2009).
-
Changes in LTP/LTD at 28
At 6 months there is a large reduction of long-term potentiation and disrupted paired pulse facilitation. No deficit at 4 months (Breyhan et al., 2009).
-
Cognitive Impairment at 27
Age-dependent impairments in working memory as measured by the Y maze and T-maze continuous alternation task. No deficit at 2 months, but deficits at 6 and 12 months compared to PS1KI littermates (Wirths et al., 2008).
Absent
-
Tangles at
Absent.
No Data
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP, PSEN1 | APP KM670/671NL (Swedish), APP V717I (London), PSEN1 M233T, PSEN1 L235P | APP: Transgenic; PSEN1: Knock-In | Alzheimer's Disease | Acceleration of extracellular Aβ deposition compared to the single transgenics. Age-dependent neuronal loss in the hippocampus with extensive neuronal loss in the CA1/2 at 10 months with detection as early as 6 months in female mice. Intraneuronal Aβ and thioflavin-S-positive deposits before neuronal loss. Astrogliosis in proximity of Aβ-positive neurons. |
Age-dependent impairments in working memory as measured by the Y maze and T-maze continuous alternation task. No deficit at 2 months, but deficits at 6 and 12 months compared to PS1KI littermates. |
APPDutch
Observed
-
Gliosis at 126
Microgliosis develops after the onset of CAA pathology and is prominent in areas adjacent to amyloid-laden vessels. There is also widespread activation of astrocytes in neocortical regions affected by CAA. These changes have been reported at 29 months of age, although the actual onset of gliosis may occur earlier than has been examined.
Absent
-
Plaques at
No plaques are observed, but CAA develops at 22-24 months.
-
Tangles at
Absent.
No Data
-
Neuronal Loss at
Unknown.
-
Synaptic Loss at
Unknown.
-
Changes in LTP/LTD at
Unknown.
-
Cognitive Impairment at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP | APP E693Q (Dutch) | APP: Transgenic | Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch type, Cerebral Amyloid Angiopathy, Alzheimer's Disease | Increased Aβ40/42 ratio. Extensive vascular Aβ deposition starting at 22-24 months appearing first in leptomeningeal vessels followed by cortical vessels, leading to smooth muscle cell degeneration, hemorrhages, and neuroinflammation. Parenchymal amyloid plaques are not observed. |
Unknown. |
APP E693Δ-Tg (Osaka)
Observed
-
Neuronal Loss at 104
Neuronal loss, as measured by NeuN staining, was observed in the CA3 region of the hippocampus at 24 months of age. Neuronal loss was not detected in the cerebral cortex at this time.
-
Gliosis at 52
At 12 months of age, microgliosis is seen in transgenic mice, as measured by the presence of Iba-1 staining in the hippocampus and cortex. Astrocytosis, as measured by GFAP-reactivity, increased starting around 18 months of age in these regions.
-
Synaptic Loss at 34
Starting around eight months of age, transgenic mice exhibit a decrease in synaptic density in the CA3 region of the hippocampus as measured by synaptophysin staining.
-
Changes in LTP/LTD at 35
By eight months of age, transgenic mice exhibit reduced short term plasticity as measured by paired-pulse facilitation in addition to reduced LTP as elicited by high frequency stimulation to the perforant pathway.
-
Cognitive Impairment at 36
By 8 months of age, transgenic mice exhibit memory impairment in the Morris water maze compared to mice expressing equivalent levels of wild-type human APP.
Absent
-
Plaques at
Extracelluar amyloid plaques are not observed out to 24 months; however, Aβ accumulates within neurons of the hippocampus and cerebral cortex starting around eight months of age.
-
Tangles at
Overt tangle pathology is not observed out to 24 months of age, but abnormal tau phosphorylation is observed starting around eight months of age.
No Data
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP | APP E693del (Osaka) | APP: Transgenic | Alzheimer's Disease | Age-dependent accumulation of Aβ oligomers within hippocampal and cortical neurons, but negligible deposits of extracellular amyloid. Abnormal tau phosphorylation, but no overt tangle pathology. Synaptic loss and gliosis in hippocampus and cerebral cortex. Late neuronal loss in the CA3 region of the hippocampus. |
Memory impairment by eight months as measured by the Morris water maze. Specifically, reduced spatial reference memory in the Morris water maze compared to mice expressing comparable levels of wild-type human APP. |
APP NL-F
Observed
-
Plaques at 26
Homozygotes develop amyloid plaques starting at 6 months in the cortex and hippocampus. Heterozygotes develop amyloidosis after 24 months. Plaques contained Aβ1-42 and pyroglutamate Aβ (Aβ3(pE)-42); Aβx-40 was a minor species.
-
Gliosis at 26
Microglia and activated astrocytes accumulate with age, starting around 6 months of age, concurrent with plaque formation.
-
Synaptic Loss at 39
Reduced synaptophysin and PSD95 immunoreactivities associated with Aβ plaques at 9-12 months.
-
Cognitive Impairment at 78
Memory impairment in homozygous mice at 18 months as measured by the Y maze test. APPNL/NL mice (with Swedish mutation only) were unimpaired at this age. No significant deficit was seen in the Morris water maze at 18 months.
Absent
-
Neuronal Loss at
Absent.
-
Tangles at
Absent; although elevated levels of phosphorylated tau are observed in dystrophic neurites around plaques.
No Data
-
Changes in LTP/LTD at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP | APP KM670/671NL (Swedish), APP I716F (Iberian) | APP: Knock-In | Alzheimer's Disease | Elevated Aβ peptides accumulating into plaques starting at 6 months. Microgliosis and astrocytosis, especially around plaques. Reduced synaptophysin and PSD-95 indicative of synaptic loss. No tangle pathology or neurodegeneration. |
Memory impairment by 18 months as measured by the Y maze. No significant impairment in the Morris water maze. |
APP NL-G-F
Observed
-
Plaques at 9
Aggressive amyloidosis; plaques develop in homozygous mice starting at 2 months with near saturation by 7 months. Aβ deposition at 4 months in heterozygous mice. Cortical and subcortical amyloidosis present.
-
Gliosis at 9
Microglia and activated astrocytes accumulate with age starting around 2 months, especially around plaques in a manner concurrent with plaque formation.
-
Synaptic Loss at 17
Reduction of synaptophysin and PSD95 immunoreactivities associated with Aβ plaques in both cortical and hippocampal areas.
-
Cognitive Impairment at 26
Memory impairment in homozygous mice by 6 months of age as measured by the Y maze.
Absent
-
Neuronal Loss at
Absent.
-
Tangles at
Absent; although phosphorylated tau is elevated in dystrophic neurites around plaques.
No Data
-
Changes in LTP/LTD at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP | APP KM670/671NL (Swedish), APP I716F (Iberian), APP E693G (Arctic) | APP: Knock-In | Alzheimer's Disease | Aggressive amyloidosis with deposition in the cortex beginning at 2 months and approaching saturation by 7 months. Aβ deposition in heterozygous mice at 4 months. Subcortical amyloidosis. Exacerbated microgliosis and astrocytosis compared to APPNL-F mice. Reduced synaptophysin and PSD-95 indicative of synaptic loss. No tangle pathology or neurodegeneration. |
Memory impairment by 6 months as measured by the Y maze. |
APPPS1
Observed
-
Neuronal Loss at 74
Global neuron loss is not observed, but modest neuron loss was found in the granule cell layer of the dentate gyrus and other subregions with high neuronal density in 17-month old animals (Rupp et al., 2011).
-
Plaques at 6
Aβ deposition begins at 6 weeks of age in the cortex and 3-4 months of age in the hippocampus (Radde et al., 2006).
-
Gliosis at 6
Activated microglia around Aβ deposits at 6 weeks as well as increased astrogliosis (Radde et al., 2006). Levels of CCL2 and TNFα increase at later ages (Lee et al., 2010).
-
Synaptic Loss at 10
Dendritic spine loss around plaques reported to begin approximately 4 weeks after plaque formation and continue for several months (Bittner et al., 2012).
-
Changes in LTP/LTD at 35
Hippocampal CA1 LTP normal at 4.5 months of age, but impaired at 8 and 15 months of age (Gengler et al., 2010).
-
Cognitive Impairment at 30
Cognitive deficits in spatial learning and memory in the Morris water maze reported at 7 months (Serneels et al., 2009). Impaired reversal learning of a food-rewarded four-arm spatial maze task observed at 8 months (Radde et al., 2006).
Absent
-
Tangles at
Phosphorylated tau-positive neuritic processes around plaques have been observed, but no mature tangles (Radde et al., 2006).
No Data
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP, PSEN1 | APP KM670/671NL (Swedish), PSEN1 L166P | APP: Transgenic; PSEN1: Transgenic | Alzheimer's Disease | Amyloid plaque deposition starts at approximately 6 weeks in the neocortex. Amyloid deposits in the hippocampus appear at 3-4 months, and in the striatum, thalamus and brainstem at 4-5 months. Phosphorylated tau-positive neuritic processes have been observed in the vicinity of all congophilic amyloid deposits, but no fibrillar tau inclusions are seen.
|
Cognitive deficits in spatial learning and memory in the Morris water maze reported at 7 months. Impaired reversal learning of a food-rewarded four-arm spatial maze task at 8 months. |
APP/PS1/rTg21221
Observed
-
Neuronal Loss at 36
Neuronal loss observed adjacent to plaques relative to more distal areas.
-
Plaques at 35
Cortical plaques observed between 8-10 months. Plaques larger than in control mice not expressing human tau.
-
Gliosis at 37
Increased astrocytosis adjacent to plaques relative to more distal areas.
-
Synaptic Loss at 40
Decreased synapse density adjacent to plaques relative to more distal areas.
Absent
-
Tangles at
No tangles. Aggregates of misfolded and phosphorylated tau observed between 8-10 months.
No Data
-
Changes in LTP/LTD at
No data.
-
Cognitive Impairment at
No data.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP, PSEN1, MAPT | APP KM670/671NL (Swedish), PSEN1: deltaE9 | APP: Transgenic; PSEN1: Transgenic; MAPT: Knock-In | Alzheimer's Disease | Tau accumulations, dystrophic neurites, astrocytosis, neuronal loss, and synapse loss were more pronounced adjacent to cortical plaques. Tangles were not observed. |
No data. |
APPsw/0; Pdgfrβ+/-
Observed
-
Neuronal Loss at 39
Progressive neuronal degeneration including reduced neurite density and reduced neuronal number in the cortex and hippocampus of APPsw/0; Pdgfrβ+/- mice at at nine months compared to age-matched APPsw/0; Pdgfrβ+/+ littermates.
-
Plaques at 39
By 9 months of age APPsw/0;Pdgfrβ+/- mice have an elevated plaque load in the cortex and hippocampus compared with age matched APPsw/0;Pdgfrβ+/+. littermates. They also have extensive cerebral amyloid angiopathy.
-
Cognitive Impairment at 41
At nine months, APPsw/0;Pdgfrβ+/- mice perform poorly on several hippocampal-dependent behavioral tests including burrowing, nest construction, and novel object recognition, compared with age-matched APPsw/0;Pdgfrβ+/+ littermates.
Absent
No Data
-
Tangles at
Although mature neurofibrillary tangles were not observed by 9 months (the oldest age assessed), the mice develop significant tau pathology, including tau hyperphosphorylation in cortical and hippocampal neurons. Pre-tangle pathology is observed, including neuronal caspase-cleaved tau, and conformational changes as indicated by the conformation-specific antibody MC1.
-
Gliosis at
Unknown.
-
Synaptic Loss at
Unknown.
-
Changes in LTP/LTD at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP, PDGFRB | APP KM670/671NL (Swedish) | APP: Transgenic; PDGFRB: Knock-Out | Alzheimer's Disease | Amyloid plaques; elevated brain interstitial human and murine Aβ due to reduced clearance of soluble Aβ, cerebral amyloid angiopathy, tau hyperphosphorylation and related pathology. Neurite loss and neuronal loss in the cortex and hippocampus. |
Age-associated cognitive impairment as measured by hippocampal-dependent tasks, including nest building, burrowing, and novel object recognition. |
APPSwDI/NOS2-/-
Observed
-
Neuronal Loss at 52
Significant neuron loss by 52 weeks in the hippocampus and subiculum, especially of neuropeptide Y neurons. Numerous Fluoro-Jade C+ neurons: 30% loss in the hippocampus, 35% loss in the subiculum (Wilcock et al., 2008).
-
Plaques at 49
Aβ deposits by 52 weeks. Particularly dense Aβ immunoreactivity in the subiculum and thalamus, including in the cerebral microvessels (Wilcock et al., 2008).
-
Tangles at 49
Extensive tau pathology by 52 weeks, including intraneuronal aggregates of hyperphosphorylated tau. Increased phosphorylated tau in bigenic mice compared to APPSwDI mice (Wilcock et al., 2008).
-
Cognitive Impairment at 53
Impairments in spatial memory by 52-56 weeks as measured by the radial arm maze and the Barnes maze. Bigenic mice more impaired than APPSwDI (Wilcock et al., 2008).
Absent
No Data
-
Gliosis at
Unknown.
-
Synaptic Loss at
Unknown.
-
Changes in LTP/LTD at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP, NOS2 | APP KM670/671NL (Swedish), APP E693Q (Dutch), APP D694N (Iowa) | APP: Transgenic; NOS2: Knock-Out | Alzheimer's Disease | Plaques especially in the thalamus and subiculum. Aggregated, hyperphosphorylated tau tangles. Neuronal loss especially of NPY neurons in the hippocampus and subiculum. More severe pathology than Tg-SwDI alone. |
Severe learning and memory deficits. Impaired spatial memory compared to Tg-SwDI as measured by the radial arm maze and the Barnes maze at 52-56 weeks. |
APP(Swedish) (R1.40)
Observed
-
Plaques at 59
By 13.5 months homozygous mice develop both parenchymal and vascular amyloid deposits which first appear in the frontal cortex. No Aβ deposition at 5 months (Lehman et al., 2003).
-
Gliosis at 61
Reactive astrocytes and microglia in 14-16 month old animals (Kulnane et al., 2001).
Absent
-
Tangles at
No mature tangles, but some changes in phosphorylated tau.
-
Changes in LTP/LTD at
Absent.
No Data
-
Neuronal Loss at
Unknown.
-
Synaptic Loss at
Unknown.
-
Cognitive Impairment at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP | APP KM670/671NL (Swedish) | APP: Transgenic | Alzheimer's Disease | By 14-16 months, homozygotes have diffuse and compact Aβ deposits in the frontal cortex, by 18-20 months plaques throughout the cortex and olfactory bulb with occasional deposits in the corpus callosum and hippocampus. No tangles, but some changes in phosphorylated tau. Reactive astrocytes and microglia by 14-16 months. |
Unknown. |
APPSwe (line C3-3)
Observed
-
Plaques at 104
Some plaque formation at advanced age (24-26 months) (Savonenko et al., 2003).
Absent
-
Cognitive Impairment at
Normal reference and working memory up to 12-14 months on congenic background (Savonenko et al., 2003).
No Data
-
Neuronal Loss at
No data.
-
Tangles at
No data.
-
Gliosis at
No data.
-
Synaptic Loss at
No data.
-
Changes in LTP/LTD at
No data.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP | APP KM670/671NL (Swedish) | APP: Transgenic | Alzheimer's Disease | Age-associated increase in Aβ40 and Aβ42 and some amyloid deposition at advanced age. |
Congenic animals showed normal reference and working memory up to 12-14 months. |
APPSwe/PSEN1(A246E)
Observed
-
Plaques at 39
By 9 months of age, amyloid plaques develop in the hippocampus and subiculum, later extending to the cortex (Borchelt et al., 1997). The striatum and thalamus are relatively spared out to 18 months of age. Amyloid pathology is more severe in female mice, with a greater amyloid burden measured at 12 and 17 months of age (Wang et al., 2003).
-
Gliosis at 52
By one year of age, reactive gliosis is observed in the cortex and hippocampus and is associated with dystrophic neurites (Borchelt et al., 1997).
-
Cognitive Impairment at 48
Age-associated cognitive impairment, as measured by the Morris water maze, was observed in 11 to 12-month-old males. Both acquisition and retention were impaired. No impairment at 3-4 months of age. At both time points mice performed normally on a position discrimination task in the T-maze (Puoliväli et al., 2002).
Absent
-
Neuronal Loss at
There was no difference in neuronal numbers in the cingulate cortex compared with wild-type mice (Xiang et al., 2002).
-
Tangles at
Not observed.
No Data
-
Synaptic Loss at
No data.
-
Changes in LTP/LTD at
No data.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP, PSEN1 | APP KM670/671NL (Swedish), PSEN1 A246E | APP: Transgenic; PSEN1: Transgenic | Alzheimer's Disease | Amyloid plaques by 9 months, starting in the hippocampus and subiculum. Plaques later develop in the cortex; the striatum and thalamus are relatively spared. Amyloid pathology is more severe in females. Dystrophic neurites and gliosis in the cortex and hippocampus. |
Poor nest building. Reduced retention in a learned passive avoidance task. Increased immobility time in forced swim task. Age-associated impairment in acquisition and retention in the Morris water maze. No impairment in a position discrimination T-maze task. |
APPswe/PSEN1dE9
Observed
-
Neuronal Loss at 35
Neuronal loss observed adjacent to plaques relative to more distal areas.
-
Plaques at 26
Occasional Aβ deposits can be found by 6 months, with abundant plaques in the hippocampus and cortex by 9 months (Jankowsky et al., 2004) and a progressive increase in plaques up to 12 months (Garcia-Alloza et al., 2006).
-
Gliosis at 26
Minimal astrocytosis at 3 months; significant astrocytosis by 6 months, especially in areas around plaques. Extensive GFAP+ staining at 15 months and later throughout the cortex (Kamphuis et al., 2012).
-
Synaptic Loss at 17
In the B6 congenic mice, age-dependent loss of synaptophysin, synaptotagmin, PSD-95, and Homer immunoreactivity in the hippocampus by 4 months (Hong et al., 2016).
-
Changes in LTP/LTD at 13
Transient long-term potentiation (t-LTP) is reduced by 3 months. The degree of impairment is not related to age from 3 to 12 months (Volianskis et al., 2008).
-
Cognitive Impairment at 52
Impairment in the Morris water maze at 12 months, specifically during acquisition of the hidden platform sub-task and the probe trial, but not in the visible platform test (Lalonde et al., 2005). At 13 months the mice commit more errors in the Morris water maze, but not at 7 months (Volianskis et al., 2008).
Absent
-
Tangles at
Not observed.
No Data
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP, PSEN1 | APP KM670/671NL (Swedish), PSEN1: deltaE9 | APP: Transgenic; PSEN1: Transgenic | Alzheimer's Disease | Occasional Aβ deposits by 6 months with abundant plaques in the hippocampus and cortex by 9 months and a progressive increase in plaques up to 12 months. No tangles. Decrease in synaptic markers and increase in complement immunoreactivity. |
Cognitive impairment (e.g., deficits in spatial memory and contextual memory). Changes in spontaneous behavior (e.g., nest-building, burrowing). High incidence of seizures. |
APPSwe/PSEN1dE9
Observed
-
Plaques at 26
Plaques are present in the hippocampus and cortex by 6 months of age.
-
Cognitive Impairment at 78
Age-related cognitive deficits. Episodic memory appears to be more sensitive than reference memory. No differences at 6 months of age, but detectable at 18 months (Savonenko et al., 2005).
Absent
-
Tangles at
Not observed.
No Data
-
Neuronal Loss at
No data.
-
Gliosis at
No data.
-
Synaptic Loss at
No data.
-
Changes in LTP/LTD at
No data.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP, PSEN1 | APP KM670/671NL (Swedish), PSEN1: deltaE9 | APP: Transgenic; PSEN1: Transgenic | Alzheimer's Disease | Elevated Aβ42 and plaques in the hippocampus and cortex. No tangles. Reduced cholinergic markers. |
Age-related cognitive deficits; episodic memory more sensitive than reference memory. No differences at 6 months, but detectable at 18 months. |
APP(V642I)KI
Observed
-
Cognitive Impairment at 117
Impairments at the water finding task at age 27-29 months, a test of long-term memory. No differences in the open field test of the elevated plus maze indicating no difference in general behavioral patterns, activity level, or emotional state.
Absent
-
Neuronal Loss at
Absent.
-
Plaques at
Absent.
-
Tangles at
Absent.
No Data
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP | APP V717I (London) | APP: Transgenic | Alzheimer's Disease | Increased Aβ42(43) relative to Aβ40 at 29 months, but without neuritic plaques, neurofibrillary tangles, massive neuronal loss, or brain atrophy. |
At 27-29 months mice displayed long-term memory deterioration. Acquisition of spatial memory is slightly affected, but no deterioration in short-term working memory. No difference in open field test or elevated plus maze suggesting no difference in overall behavioral patterns or activity levels. |
APP(V717I)
Observed
-
Plaques at 43
Plaques start in the cortex and subiculum at ~10 months. Diffuse amyloid deposits and compact neuritic plaques at 13-18 months especially in the hippocampus and cortex, with occasional deposits in the thalamus and fimbria, external capsule, pontine nuclei, and white matter (Moechars et al., 1999). Prominent amyloid deposits in brain vessels after 15 months (Van Dorpe et al, 2000).
-
Gliosis at 43
GFAP, microglial activation, and other markers of brain inflammation are elevated by 10 months.
-
Changes in LTP/LTD at 26
Significant deficit in LTP in CA1 region of the hippocampus at 6 months.
-
Cognitive Impairment at 26
From the age of 6 months, spatial and non-spatial orientation and memory deficits by Morris water maze and other tests. Also deficits in associative learning.
Absent
-
Neuronal Loss at
Absent.
-
Tangles at
Dystrophic neurites containing hyperphosphorylated tau, but no tangle pathology.
No Data
-
Synaptic Loss at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP | APP V717I (London) | APP: Transgenic | Alzheimer's Disease, Cerebral Amyloid Angiopathy | Plaques start in the subiculum, spreading to the frontal cortex as dense and diffuse aggregates. Prominent amyloid deposits in brain vessels after 15 months. Microbleeds. Amyloid-associated inflammation. CSF Aβ42/Aβ40 ratio decreases from 15 months. Dystrophic neurites containing hyperphosphorylated tau, but no tangle pathology. |
From the age of 6 months, spatial and non-spatial orientation and memory deficits by Morris water maze. Impaired associative learning. Increased agitation/anxiety from 8 weeks. Reduced ambulation, especially with age. Hyperactivity and aggression. |
APP(V717I) x PS1(A246E)
Observed
-
Plaques at 17
Plaques start in cortex, hippocampus and subiculum at 4-6 months.
-
Gliosis at 20
Elevated GFAP, microglial activation, and other markers of brain inflammation increase as of 4.5 months.
-
Changes in LTP/LTD at 26
Significant deficit in LTP in CA1 region of the hippocampus at 6 months.
-
Cognitive Impairment at 22
From the age of 5 months, spatial and non-spatial orientation and memory deficits by Morris water maze and other tests. Also deficits in associative learning.
Absent
-
Tangles at
Dystrophic neurites containing hyperphosphorylated murine tau, but no tangle pathology.
No Data
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP, PSEN1 | APP V717I (London), PSEN1 A246E | APP: Multi-transgene; PSEN1: Transgenic | Alzheimer's Disease, Cerebral Amyloid Angiopathy | Soluble, oligomeric Aβ at 2 months and increases with age. Amyloid plaques at 6-9 months, earlier than APP(V717I) single transgenics. Plaques start in the subiculum and spread to the frontal cortex. Amyloid-associated inflammation. CAA pathology at 8 months; microbleeds at 12-15 months. Dystropic neurites containing hyperphosphorylated tau, but no tangle pathology. |
From the age of 5 months, spatial and non-spatial orientation and memory deficits by Morris Water Maze. Impaired associative learning, hyperactivity, anxiety, and aggression. |
Arc48 (APPSw/Ind/Arc)
Observed
-
Plaques at 9
Parenchymal neuritic plaques by 2 months with prominent plaque deposition in the hippocampus by 3-4 months. Abundant mature thioflavin-S positive plaques with dystrophic neurites by 10-12 months (Cheng et al., 2007).
-
Gliosis at 13
Reactive astrocytosis at 3-4 months in the dentate gyrus as demonstrated by GFAP immunoreactivity (Cheng et al., 2007).
-
Cognitive Impairment at 13
At 3-4 months the Arc48 mouse was able to learn a task involving escape to a cued platform in the Morris water maze, but were impaired in the ability to use extramaze cues to navigate to the hidden platform (Cheng et al., 2007).
Absent
-
Tangles at
Absent.
No Data
-
Neuronal Loss at
Unknown.
-
Synaptic Loss at
Unknown.
-
Changes in LTP/LTD at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP | APP KM670/671NL (Swedish), APP V717F (Indiana), APP E693G (Arctic) | APP: Transgenic | Alzheimer's Disease, Cerebral Amyloid Angiopathy | Parenchymal neuritic plaques by 2 months accompanied by dystrophic neurites. Prominent hippocampal Aβ deposition by 3-4 months. Relatively low Aβ42/Aβ40 ratio. Comparable cerebrovascular amyloid deposition to J20. |
At 3-4 months the Arc48 mouse was able to learn a task involving escape to a cued platform in the Morris water maze, but had an impaired ability to use extramaze cues to navigate to the hidden platform. |
ArcAβ
Observed
-
Plaques at 39
Between 9 and 15 months of age β-amyloid plaques became prominent. Plaques had a characteristic dense core morphology which differed from the cotton wool-like structure of plaques seen with the Swedish mutation alone (Knobloch et al., 2007).
-
Changes in LTP/LTD at 15
LTP is severely impaired in slices from 3.5 and 7.5 month old mice. LTP and basal synaptic transmission were normal in slices from one month old mice (Knobloch et al., 2007).
-
Cognitive Impairment at 26
Cognitive impairment measured from the age of 6 months in the Morris water maze and Y-maze, as well as in active avoidance behavior (Knobloch et al., 2007).
Absent
-
Tangles at
Absent.
No Data
-
Synaptic Loss at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP | APP KM670/671NL (Swedish), APP E693G (Arctic) | APP: Transgenic | Alzheimer's Disease | At 6 months intracellular punctate deposits of Aβ abundant in cortex and hippocampus, but overt β-amyloid plaques not apparent until 9-15 months. Severe CAA also present at this age with dense Aβ aggregates in blood vessels walls and spreading into the parenchyma. | Cognitive impairments from the age of 6 months measured in the Morris water maze and Y-maze. |
ARTE10
Observed
-
Plaques at 13
Robust and reliable plaque pathology as early as 3 months in homozygotes, 5 months in hemizygotes. Plaques start in the anterior neocortex and subiculum, spreading to other brain regions (e.g. hippocampus, thalamus, amygdala). Congophilic dense-core plaques are abundant, with lower levels of diffuse plaques and some cerebral amyloid angiopathy.
-
Gliosis at 22
Glial activation, including reactive astrocytes and activated microglia, is present in areas around plaques by 5 months of age in homozygous animals, later in hemizygotes.
-
Synaptic Loss at 13
Decreased expression of synaptophysin mRNA in the brain by 3-4 months of age in both hemizygous and homozygous animals.
-
Cognitive Impairment at 52
Select, paradigm-dependent, deficits in learning and memory, especially episodic memory, by 12 months in homozygous and hemizygous mice.
Absent
-
Neuronal Loss at
Outright neuronal loss has not been documented, but substantial degeneration of dendritic arbors occurs by 10-14 months of age in hippocampal neurons.
-
Tangles at
No tangles or neuropil threads, but some hyperphosphorylated tau by eight months in dystrophic neurites.
No Data
-
Changes in LTP/LTD at
Unknown; however, hippocampal neurons exhibit substantial changes in electrophysiological properties by 10-14 months of age, including hyperexcitability in the form of increased firing of action potentials and a more efficient transition from solitary firing to bursting.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP, PSEN1 | APP KM670/671NL (Swedish), PSEN1 M146V | APP: Transgenic; PSEN1: Transgenic | Alzheimer's Disease | Robust early plaque development (by 3 months in homozygotes, 5 months in hemizygotes), predominantly congophilic dense-core amyloid plaques surrounded by dystrophic neurites and gliosis. Some diffuse plaques and cerebral amyloidosis. No tau tangles. Neurons have reduced dendritic length, surface area, and branches. |
Age-related learning and memory deficits, especially episodic memory, in select paradigm-specific tasks by 12 months. |
BRI-Aβ42 (BRI2-Aβ42)
Observed
-
Plaques at 13
Detergent-insoluble amyloid-β and cored plaques as early as three months in the cerebellum. Variable forebrain pathology later with extracellular Aβ plaques in the hippocampus and entorhinal/piriform cortices by 12 months. Extensive congophillic amyloid angiopathy.
-
Gliosis at 13
Plaque-associated reactive gliosis as measured by GFAP immunostaining.
Absent
-
Neuronal Loss at
Absent.
-
Tangles at
Absent.
-
Cognitive Impairment at
On a mixed (C57/B6//C3H) background hemizygous mice have intact cognition as measured by fear conditioning at 12 months and 14-17 months despite accumulating amyloid.
No Data
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| Transgenic | Alzheimer's Disease, Cerebral Amyloid Angiopathy | Detergent-insoluble amyloid-β appearing with age and cored plaques as early as 3 months in the cerebellum. Variable forebrain pathology later with extracellular Aβ plaques in the hippocampus and entorhinal/piriform cortices at 12 months. Age-associated congophillic amyloid angiopathy. No tangles or neuronal loss. |
On a mixed (C57/B6//C3H) background hemizygous mice have intact cognition as measured by fear conditioning at 12 months and 14-17 months despite accumulating amyloid. |
E2FAD
Observed
-
Plaques at 17
Plaques develop in the subiculum and deep cortical layers by 4 months.
-
Gliosis at 26
Microgliosis and astrocytosis in the subiculum and cortex at 6 months.
-
Synaptic Loss at 17
Protein levels of NMDA receptor subunits decreased from 2 to 6 months.
Absent
No Data
-
Neuronal Loss at
No data.
-
Tangles at
No data.
-
Changes in LTP/LTD at
No data.
-
Cognitive Impairment at
E2FAD mice had performance in learning and memory tasks comparable to E3FAD animals and better than E4FAD mice.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APOE, APP, PSEN1 | APP KM670/671NL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V | APOE: Knock-In; APP: Transgenic; PSEN1: Transgenic | Alzheimer's Disease | Amyloid plaques starting at 4 months and increasing with age. Gliosis and loss of synaptic proteins. |
In the Y maze and Morris water maze, E2FAD mice performed better than E4FAD mice, and were comparabile to E3FAD mice. |
E3FAD
Observed
-
Plaques at 17
Plaques develop in the subiculum and deep cortical layers by 4 months.
-
Gliosis at 26
Microgliosis and astrocytosis in the subiculum and cortex at 6 months.
-
Synaptic Loss at 17
Protein levels of NMDA receptor subunits decreased from 2 to 6 months.
Absent
No Data
-
Neuronal Loss at
No data.
-
Tangles at
No data.
-
Changes in LTP/LTD at
No data.
-
Cognitive Impairment at
E3FAD mice had performance in learning and memory tasks comparable to E4FAD and E2FAD animals.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APOE, APP, PSEN1 | APP KM670/671NL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V | APOE: Knock-In; APP: Transgenic; PSEN1: Transgenic | Alzheimer's Disease | Amyloid plaques starting at 4 months and increasing with age. Gliosis and loss of synaptic proteins. |
In the Y maze and Morris water maze E3FAD mice performed better than E4FAD mice, and were comparabile to E2FAD mice. |
E4FAD
Observed
-
Plaques at 17
Plaques develop in the subiculum and deep cortical layers by 4 months.
-
Gliosis at 26
Microgliosis and astrocytosis in the subiculum and cortex at 6 months.
-
Synaptic Loss at 17
Decreased protein levels of PSD95 and NMDA receptor subunits by 4 months.
-
Cognitive Impairment at 8
Modest learning deficits in the Morris water maze by 2 months. Progressive decrease in performance on learning and memory tasks.
Absent
No Data
-
Neuronal Loss at
No data.
-
Tangles at
No data.
-
Changes in LTP/LTD at
No data.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APOE, APP, PSEN1 | APP KM670/671NL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V | APOE: Knock-In; APP: Transgenic; PSEN1: Transgenic | Alzheimer's Disease | Amyloid plaques starting at 4 months and increasing with age. Gliosis and loss of synaptic proteins. |
Age-dependent learning and memory deficits in the Y maze and Morris water maze. |
htau
Observed
-
Neuronal Loss at 43
Decrease in cortical thickness and reduced cell number between 10 and 14 months of age. Increased ventricle size increased from age eight months to 18 months. Decrease in the thickness of the corpus callosum (Andorfer et al., 2005).
-
Tangles at 39
Aggregated tau and paired helical filaments detectable at nine months by immunoelectron microscopy, although paired helical filaments of aggregated insoluble tau can be isolated from brain tissue as early as two months. Tau first redistributes from axons to cell bodies. Hyperphosphorylated tau begins to accumulate by six months, and increases further by 13 and 15 months (Andorfer et al., 2003).
-
Changes in LTP/LTD at 52
In hippocampal slices, LTP induced by high frequency stimulation (HFS) was normal at four months but abolished by 12 months. LTP induced by theta burst stimulation (TBS) was normal at both ages. Paired-pulse ratio (PPR) was unaffected at four months, but increased at 12 months compared with controls, suggesting a decrease in probability of transmitter release (Polydoro et al., 2009).
-
Cognitive Impairment at 26
Abnormal spatial learning in six-month-old mice compared with control mice (Phillips et al., 2011). Normal object recognition and spatial learning and memory by MWM at four months, but deficits by 12 months (Polydoro et al., 2009). Impaired burrowing relative to control mice occurs by four months (Geiszler et al., 2016).
Absent
No Data
-
Gliosis at
Unknown.
-
Synaptic Loss at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| MAPT | MAPT: Knock-Out; MAPT: Transgenic | Alzheimer's Disease, Frontotemporal Dementia | Age-associated tau pathology, including redistribution of tau to cell bodies and dendrites, phosphorylated tau, accumulation of aggregated paired helical filaments, and ultimately thioflavin-S positive neurofibrillary tangles. Pathology most severe in neocortex and hippocampus, and minimal in the brain stem and spinal cord. Some neuronal loss. |
Normal object-recognition memory and spatial learning/memory (as assessed by the Morris Water Maze) at four months, but impaired at 12 months (Polydoro et al., 2009). |
hTau-A152T
Observed
-
Neuronal Loss at 87
Neuron loss in the hippocampus was observed by 20 months.
-
Gliosis at 17
Astrocytosis, but no differences in microglia.
-
Cognitive Impairment at 74
In the Morris water maze, performance was impaired after 17 months of age. Nest building was impaired at 10-14 months. Social interaction, anxiety, exploratory behavior, and motor functions were unaltered.
Absent
-
Tangles at
Abnormal accumulations of soluble tau were observed, but not tangles or tangle-like structures.
-
Changes in LTP/LTD at
Unchanged at 20 months.
No Data
-
Plaques at
No data.
-
Synaptic Loss at
No data.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| MAPT | MAPT A152T | MAPT: Transgenic | Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy | Tangles or dense tau inclusions not observed. Abnormal accumulations of soluble tau. Age-dependent neuronal loss was observed in the hippocampus. |
Age-dependent learning and memory deficits in the Morris water maze. Nest building impaired. Social interaction, anxiety, exploratory behavior, and motor functions were normal. |
hTau-AT (hTau40-AT)
Observed
-
Neuronal Loss at 52
Neuron loss in the hippocampus and cortex at 12 months.
-
Tangles at 13
Tangles in hippocampus, cortex, and spinal cord starting at 3 months with age-dependent increases. Hyperphosphorylation, conformation changes, and mislocalization.
-
Gliosis at 43
Astrocytosis and microgliosis at 10 months.
-
Synaptic Loss at 87
Synaptophysin, but not PSD95, decreased in hippocampus and cortex at 12 months. By Golgi staining, spines unchanged in CA1 at 10 months, increased in CA3 at 12 months, and decreased in CA1 and CA3 at 16 months.
-
Cognitive Impairment at 70
No change at 10 months but at 16 months deficits in learning and memory (Morris water maze).
Absent
-
Changes in LTP/LTD at
Unchanged at 12 months.
No Data
-
Plaques at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| MAPT | MAPT A152T | MAPT: Knock-In | Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy | Tangles in hippocampus, cortex, and spinal cord at 3 months with age-dependent increases. Tau hyperphosphorylation, conformation changes, and mislocalization observed. Age-dependent loss of synapses. |
Age-dependent learning and memory deficits in the Morris water maze. Motor functions normal. |
hTau.P301S
Observed
-
Neuronal Loss at 13
Neuronal loss starting at 3 months. Loss is especially prominent in the spinal cord with notable loss of superficial cortical neurons as well (Hampton et al., 2010).
-
Tangles at 17
Neurofibrillary tangles detected as early as 4 months of age.
-
Gliosis at 22
Astrocytosis, as measured by GFAP reactivity, in 6 month-old animals. Microglial activation in the brain stem and spinal cord of 5 month-old animals by OX42 staining (Bellucci et al., 2004).
-
Cognitive Impairment at 11
Memory deficit starting at 2.5 months as assessed by the Morris water maze (Xu et al., 2014), but no deficit at 2 months (Scattoni et al., 2010).
Absent
-
Plaques at
Absent.
No Data
-
Synaptic Loss at
Unknown.
-
Changes in LTP/LTD at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| MAPT | MAPT P301S | MAPT: Transgenic | Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy | Age-dependent hyperphosphorylation of tau and conformational changes leading to neurofibrillary tanglelike pathology in the cerebral cortex, hippocampus, brain stem, and spinal cord. Neurodegeneration, especially in the spinal cord, accompanied by astrocytosis. |
Early motor impairment, including abnormal clasping and rotarod deficit at 4 months, with nearly complete deficit at 5 months. Deficits progress to severe paraparesis. Disinhibition and hyperactivity at 2 to 3 months. |
J20 (PDGF-APPSw,Ind)
Observed
-
Neuronal Loss at 12
Cell loss varies by brain region. No significant neuronal loss was observed in the CA3 region of the hippocampus at 6, 12, 24 and 36 weeks of age nor in the CA1 region at 6 weeks; however, at 12, 24, and 36 weeks significant neuronal loss was observed in the CA1 region compared to age-matched wild-type animals (Wright et al., 2013).
-
Plaques at 22
At 5-7 months of age diffuse amyloid-β plaques deposit in the dentate gyrus and neocortex. Amyloid deposition is progressive with widespread plaques by 8-10 months. Aβ puncta are deposited in the hippocampus as early as 1 month (Hong et al., 2016).
-
Gliosis at 24
At 24 and 36 weeks a significant increase in the number of reactive GFAP+ astrocytes and CD68+ microglia was observed in the hippocampi of J20 mice compared to age-matched wild-type controls. No significant difference was observed at 6 and 12 weeks (Wright et al., 2013).
-
Synaptic Loss at 15
Age-dependent loss of synaptophysin, synaptotagmin, PSD-95, and homer immunoreactivity in the hippocampus by 3 months; synapse loss was confirmed by electron microscopy. No significant difference was seen at 1 month (Hong et al., 2016).
-
Changes in LTP/LTD at 13
Basal synaptic transmission is impaired between 3-6 months; extracellularly recorded field EPSPs at the Schaffer collateral to CA1 synapse in acute hippocampal slices were on average smaller in amplitude than those seen in wild-type mice. Significant deficits in LTP at the Schaffer collateral–CA1 synapse compared with control mice at 3-6 months (Saganich et al., 2006).
-
Cognitive Impairment at 16
Deficits in spatial memory and learning appear as the mice age. As early as 16 weeks mice demonstrate spatial reference memory deficits as measured by the radial arm maze (Wright et al., 2013). By 6-7 months deficits appear in spatial memory retention and acquisition in the water maze (Palop et al., 2003).
Absent
-
Tangles at
Absent.
No Data
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP | APP KM670/671NL (Swedish), APP V717F (Indiana) | APP: Transgenic | Alzheimer's Disease | Age-dependent formation of Aβ plaques. Dystrophic neurites associated with plaques. No tangles. Variable cell loss. Decrease in synaptic markers and increase in complement immunoreactvity. |
Learning and memory deficits are age-dependent and may appear as early as 16 weeks. Hyperactivity and increased time in the open arm of the elevated plus maze than wild-type mice indicating lower levels of anxiety, but has not been universally replicated. |
JNPL3(P301L)
Observed
-
Neuronal Loss at 43
Neuronal loss, especially in the spinal cord, most prominent in the anterior horn (Lewis et al., 2000).
-
Tangles at 20
Neurofibrillary tangles develop in an age and gene-dose dependent manner; as early as 4.5 months in homozygotes and 6.5 months in heterozygotes. Tangles and Pick-body-like neuronal inclusions in the amygdala, septal nuclei, preoptic nuclei, hypothalamus, midbrain, pons, medulla, deep cerebellar nuclei and spinal cord (Lewis et al., 2000).
-
Gliosis at 43
Astrogliosis (as measured by GFAP reactivity) in brainstem, diencephalon, and basal telencephalon by 10 months (Lewis et al., 2000).
Absent
-
Plaques at
Absent.
No Data
-
Cognitive Impairment at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| MAPT | MAPT P301L | MAPT: Transgenic | Frontotemporal Dementia, Progressive Supranuclear Palsy, Alzheimer's Disease | Age and gene-dose dependent development of neurofibrillary tangles as early as 4.5 months in homozygotes and 6.5 months in heterozyotes. Tangles and Pick-body-like inclusions in the amygdala, hypothalamus, pons, medulla, and spinal cord among other areas. Neuronal loss, especially in the spinal cord. |
By 10 months, 90% developed motor and behavioral disturbances including limb weakness, hunched posture, decrease in grooming and vocalization. |
mThy-1 3R Tau (line 13)
Observed
-
Neuronal Loss at 34
Neuronal loss occurred by 8-10 months as evidenced by decreased NeuN staining in the dentate gyrus and CA3 regions of the hippocampus. Neocortical volume also decreased.
-
Tangles at 34
Pick-body like inclusions of aggregated tau appeared in the hippocampus and cortex by 8-10 months. Inclusions were positive for Bielchowsky silver stain but negative for Gallyas-silver stain and Thioflavin-S.
-
Gliosis at 35
Astrogliosis was seen by 8-10 months in the neocortex and hippocampus. Some GFAP+ astrocytes also contained 3R tau.
-
Cognitive Impairment at 26
By 6-8 months memory impairment was evident as a failure to habituate to a novel environment. This deficit was not present at 3-4 months. At 8-10 months, transgenics also took longer than wild-type mice to find the hidden platform in the Morris water maze.
Absent
-
Plaques at
Absent.
No Data
-
Synaptic Loss at
Synapto-dendritic damage manifested as reduced dendritic density, reduced MAP2 immunoreactivity, and accumulation of 3R tau in dendrites.
-
Changes in LTP/LTD at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| MAPT | MAPT L266V, MAPT G272V | MAPT: Transgenic | Frontotemporal Dementia, Pick's disease, Alzheimer's Disease | Accumulation of 3R tau in neurons of the cortex and hippocampus. Pick body-like tau aggregates and neuronal loss in the hippocampus and cortex. Astrogliosis, with some 3R tau in GFAP-positive astrocytes. Synapto-dendritic changes and mitochondrial pathology. |
Age-related memory and motor deficits as assessed by habituation to a novel environment, the Morris water maze, and the round beam test. |
mThy1-hAPP751 (TASD41)
Observed
-
Plaques at 13
Plaques start at 3-6 months in the frontal cortex and become widespread with age, affecting the piriform and olfactory cortices, hippocampus, and thalamus (Rockenstein et al., 2001; Havas et al., 2011).
-
Gliosis at 27
Inflammation related to activated microglia (increased CD11) and reactive astrocytes (increased GFAP) is significant by 6 months and increases with age.
-
Synaptic Loss at 52
Dystrophic neurites and synaptic loss starting at 12 months.
-
Cognitive Impairment at 26
Cognitive impairment observed by 6 months by Morris Water Maze (Rockenstein et al., 2005).
Absent
-
Neuronal Loss at
Absent.
-
Tangles at
Absent.
No Data
-
Changes in LTP/LTD at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP | APP KM670/671NL (Swedish), APP V717I (London) | APP: Transgenic | Alzheimer's Disease | Age-dependent increases in Aβ40 and Aβ42, with Aβ42 > Aβ40. Plaques at an early age, starting at 3-6 months in the frontal cortex. At 5-7 months, size and number of plaques increased in the frontal cortex, and dense amyloid deposits appear in hippocampous, thalamus, and olfactory region. |
Age-associated impairment in spatial memory and learning in the water maze task and habituation in the hole-board task, with significant deficits at 6 months of age. Some gender-specific differences in open field exploration. |
NSE-APP751
Observed
-
Plaques at 8
Aβ deposits were observed as early as two months of age. These deposits were diffuse and extracellular and had a “cotton-like” appearance. Classic mature plaques were not observed.
-
Gliosis at 95
Gliosis was noted in a single 22-month-old animal with extensive Aβ deposits (Higgins et al., 1994).
-
Cognitive Impairment at 52
Deficits in spatial memory and learning appear as the mice age. At 12 months the mice demonstrate learning and memory deficits as measured by a water-maze task and in spontaneous alternation in a Y maze (Moran et al., 1995). At six months cognition is largely normal.
Absent
-
Neuronal Loss at
Cell death was not formally assessed, however, overt neuronal death was not seen.
-
Tangles at
Classic tangles were not observed, but aberrant tau immunoreactivity was observed as early as two months.
No Data
-
Synaptic Loss at
Unknown.
-
Changes in LTP/LTD at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP | APP: Transgenic | Alzheimer's Disease | Age-dependent increase in Aβ deposits and tau immunoreactivity. |
Learning and memory deficits are age-dependent as assessed on spontaneous alternation in a Y maze and in the water-maze task. |
PDAPP(line109)
Observed
-
Plaques at 26
In heterozygous mice no plaque pathology at 4-6 months. At 6-9 months mice begin to exhibit deposits of human Aβ in the hippocampus, corpus callosum, and cerebral cortex. Plaques become more extensive with age and vary in size and structure including diffuse irregular plaques and compact cored plaques (Games et al., 1995).
-
Gliosis at 26
GFAP-positive astrocytes and activated microglia associated with plaques (Games et al., 1995).
-
Synaptic Loss at 35
Decreased synaptic density in the dentate gyrus as measured by synaptophysin immunoreactivity. Also decreased dendritic density as measured by MAP2 immunoreactivity (Games et al., 1995).
-
Changes in LTP/LTD at 17
Alterations in LTP induced by theta burst stimulation at 4-5 months which is prior to plaque formation; although the potentiation immediately after TBS was comparable to control mice, the potentiation decayed more rapidly in PDAPP mice. Also paired pulse facilitation was enhanced. Responses to high frequency stimulation bursts were distorted (Larson et al., 1999).
-
Cognitive Impairment at 13
Deficits in a variety of memory paradigms from a young age. Robust deficits in the radial arm maze at 3 months (deficits appear before amyloid plaque deposits). Object recognition, 6, 9-10 months. Operant learning, 3, 6 months (Dodart et al., 1999).
Absent
-
Neuronal Loss at
Absent.
-
Tangles at
No paired helical filaments or aggregates, but phosphorylated tau immunoreactivity is observed in dystrophic neurites after 14 months (Masliah et al., 2001).
No Data
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP | APP V717F (Indiana) | APP: Transgenic | Alzheimer's Disease | Amyloid plaques in the hippocampus, cerebral cortex. Gliosis. Dystrophic neurites. Decreased synaptic and dendritic density in the hippocampus. |
Deficits in a variety of memory paradigms from a young age. Deficits in the radial arm maze at 3 months (before plaques), object recognition, operant learning, spatial reference memory (starting at 3-4 months), cued fear conditioning at 11 months. |
PDGF-APP(WT) (line I5)
Observed
-
Synaptic Loss at 9
By 2-4 months of age, there is a decrease in synaptophysin-immunoreactive presynaptic terminals compared to nonTg controls. Synaptophysin immunoreactivity decreases further with age.
Absent
-
Neuronal Loss at
Not observed.
-
Tangles at
Not observed.
No Data
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP | APP: Transgenic | Alzheimer's Disease | Expression of human APP in the brain especially in the neocortex and hippocampus. No plaques up to 24 months. |
Unknown. |
PLB1-triple (hAPP/hTau/hPS1)
Observed
-
Gliosis at 52
Increased inflammation (GFAP labelling) detected at 12 months in cortex and hippocampus (Platt, unpublished observation).
-
Changes in LTP/LTD at 26
Impairments in long-term and short-term hippocampal plasticity. LTP following theta-burst stimulation decayed faster and paired-pulse facilitation was reduced relative to wild-type mice at both six and 12 months of age. Synaptic transmission impacted at 12 months.
-
Cognitive Impairment at 22
Social recognition memory was impaired by five months and further impaired by 12 months. Similarly, object recognition memory was impaired by eight months. Spatial learning impairments were seen later; at 12 months deficits in spatial acquisition learning were seen in the open field water maze that were not apparent at 5 months.
Absent
-
Neuronal Loss at
Absent.
-
Plaques at
Sparse plaques out to 21 months of age. Only marginally increased compared with wild-types and overall very low compared to over-expression models. However, Aβ accumulated intracellularly and also formed oligomers.
-
Tangles at
No overt tangle pathology; however, hyyperphosphorylated tau accumulated in the hippocampus and cortex from six months of age.
No Data
-
Synaptic Loss at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP, MAPT, PSEN1 | APP V717I (London), APP KM670/671NL (Swedish), PSEN1 A246E, MAPT P301L, MAPT R406W | APP: Multi-transgene; MAPT: Multi-transgene; PSEN1: Multi-transgene | Alzheimer's Disease | Age-related neuropathology including intraneuronal and oligomeric Aβ accumulation and hyperphosphorylated tau in the hippocampus and cortex from six months. Minimal amyloid plaques up to 21 months. Subtle tau pathology, but no overt tangles. Cortical hypometabolism with increased metabolic activity in basal forebrain and ventral midbrain by FDG-PET/CT. |
Cognitive deficits in recognition memory and spatial learning emerging between five and 12 months. Impairments in hippocampal plasticity. |
PLB4 (hBACE1)
Observed
-
Gliosis at 52
Increased GFAP-positive astrocytes at 12 months of age in the dentate gyrus, CA1 region of the hippocampus, and the piriform cortex. Gliosis is suspected to begin earlier than 12 months.
-
Cognitive Impairment at 13
Impaired spatial representation in a habituation task by 3 months of age. By 6 months, impaired learning and memory by a variety of tasks including the Y-maze, Morris water maze, and a test of the social transmission of food preference. These effects appear to be distinct from reduced motor activity and reduced anxiety.
Absent
-
Plaques at
Plaques virtually absent, minimal small sparse plaques. However, prominent extracellular Aβ staining surrounding neuronal cell bodies, including Aβ multimers (e.g. Aβ*56 and Aβ hexamers).
-
Tangles at
Preliminary analysis did not find abnormal phosphorylation or conformational changes in tau.
No Data
-
Neuronal Loss at
Unknown.
-
Synaptic Loss at
Unknown.
-
Changes in LTP/LTD at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| BACE1 | BACE1: Transgenic | Alzheimer's Disease | Elevated extracellular multimeric Aβ, including Aβ*56 and Aβ hexamers, in the absence of plaques. At 12 months of age, astrogliosis was observed in a region- and genotype-dependent manner, especially in the dentate gyrus, hippocampal CA1, and piriform cortex. No overt tau pathology. |
Largely intact motor coordination and gait (Rotarod, CatWalk). Age-associated changes in multiple measures of learning and memory. Early deficits in habituation to a novel environment and semantic-like memory (three-four months). Impaired spatial learning and long-term reference (Morris water maze) and working memory (Y-maze) at six months, distinct from reduced locomotor activity and anxiety. |
PS1 cKO
Observed
-
Cognitive Impairment at 22
Mild impairment of spatial learning and memory in the Morris water maze observed in 5 month-old mice (Yu et al., 2001).
Absent
-
Neuronal Loss at
Absent.
-
Plaques at
Absent.
-
Tangles at
Absent.
-
Changes in LTP/LTD at
Mice at 3-6 months of age exhibit normal paired-pulse facilitation, LTP, and LTD in the Schaffer collateral pathway of the hippocampus (Yu et al., 2001).
No Data
-
Gliosis at
Unknown.
-
Synaptic Loss at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| PSEN1 | PSEN1: Conditional Knock-out | Alzheimer's Disease | Reduction in Aβ40 and Aβ42 peptides; accumulation of APP C-terminal fragments. |
Subtle but significant deficits in long-term spatial memory in the Morris water maze. |
PS2APP
Observed
-
Plaques at 26
Age-associated development of plaques: none at 3 months, overt Aβ deposition at approximately 6 months, with heavy plaque load in the hippocampus, frontal cortex, and subiculum at 10 months (Ozmen et al., 2009; Weidensteiner et al. 2009).
-
Gliosis at 26
Gliosis at 6 months (personal communication, Laurence Ozmen).
-
Changes in LTP/LTD at 43
A strong increase in LTP and post-tetanic potentiation induced by tetanic stimulation in hippocampal slices of 10 month-old animals compared to wild-type mice (Poirier et al., 2010).
-
Cognitive Impairment at 35
Cognitive impairment is detected by the Morris water maze (probe trial 2) at 8 and 12 months of age, not at 3 months (personal communication Laurence Ozmen).
Absent
-
Tangles at
Absent.
No Data
-
Neuronal Loss at
Unknown.
-
Synaptic Loss at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP, PSEN2 | APP KM670/671NL (Swedish), PSEN2 N141I (Volga German) | APP: Transgenic; PSEN2: Transgenic | Alzheimer's Disease | Age-associated development of plaques: none at 3 months, overt Aβ deposition in the brain at approximately 6 months, with heavy plaque load in the hippocampus, frontal cortex, and subiculum at 10 months. Aβ deposits in blood vessels were sporadic, mainly in large vessels. Cerebral amyloid deposits correlate with levels of the human APP transcript at 12 months. |
Cognitive impariment detected by the Morris water maze at 8 and 12 months of age, but not at 3 months. |
PS2APP (PS2(N141I) x APPswe)
Observed
-
Plaques at 39
Rare amyloid deposits at 5 months, with consistent deposits in the subiculum and frontolateral cortices by 9 months. Plaques increase in number and distribution over time, spreading throughout the neocortex and hippocampus as well as the amygdala and thalamic and pontine nuclei (Richards et al., 2003).
-
Gliosis at 39
An inflammatory response indicated by the presence of activated microglia and astrocytes begins around 9 months. The onset, distribution, and abundance of activated microglia and astrocytes correlate with Aβ deposition.
-
Cognitive Impairment at 35
Age-associated cognitive impairment from 8 months with impaired acquisition of spatial learning in the water maze (Richards et al., 2003).
Absent
-
Tangles at
Absent.
-
Changes in LTP/LTD at
No difference in LTP in the dentate gyrus at 3 and 10 months compared to wild-type mice (Richards et al., 2003).
No Data
-
Neuronal Loss at
Unknown.
-
Synaptic Loss at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP, PSEN2 | APP KM670/671NL (Swedish), PSEN2 N141I (Volga German) | APP: Transgenic; PSEN2: Transgenic | Alzheimer's Disease | Rare amyloid deposits at 5 months, with consistent deposits in the subiculum and frontolateral cortices by 9 months. Plaques increase in number and distribution with time, spreading throughout the neocortex and hippocampus as well as the amygdala and thalamic and pontine nuclei. The distribution and abundance of activated microglia and astrocytes correlate with Aβ deposition. |
Mice develop age-associated cognitive impairment from 8 months with impaired acquisition of spatial learning in the water maze. |
PS/APP
Observed
-
Neuronal Loss at 79
Neuronal loss in the CA1 region of the hippocampus has been reported at 22 months accompanied by reduced glucose utilization (Sadowski et al., 2004).
-
Plaques at 26
Large amounts of Aβ accumulate in the cerebral cortex and hippocampus, starting around 6 months and increasing with age. Other brain regions are affected later. Both diffuse and fibrillar plaques form (Gordon et al., 2002).
-
Gliosis at 26
GFAP-positive astrocytes appear first in the cortex in the vicinity of the developing Aβ deposits. Numbers increase with age, becoming confluent. Numbers of resting microglia (positive for complement receptor-3) increase in the vicinity of deposits at 6 months, but activated microglia (positive for MHC-II) are negligible before 12 months and more variable (Gordon et al., 2002).
-
Cognitive Impairment at 12
Double and single transgenic mice had reduced spontaneous alternation performance in a “Y” maze, a test of spatial memory, at 12-14 weeks, before substantial Aβ deposition (Holcomb et al., 1998). Progressive age-related cognitive impairment is seen later in select tasks (e.g. water maze acquisition and radial arm water maze working memory)(Arendash et al., 2001).
Absent
-
Tangles at
Neurofibrillary tangles are not associated with this model, but hyperphosphorylated tau is detected, starting at 24 weeks, appearing as punctate deposits near amyloid deposits in the cortex and hippocampus (Kurt et al., 2003).
No Data
-
Synaptic Loss at
Unknown.
-
Changes in LTP/LTD at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP, PSEN1 | APP KM670/671NL (Swedish), PSEN1 M146L (A>C) | APP: Transgenic; PSEN1: Transgenic | Alzheimer's Disease | Aβ accumulates in the cerebral cortex and hippocampus starting ~6 months and increasing with age. Other regions affected later. Deposition occurs in white matter, cerebrovasculature, and grey matter in the form of diffuse and fibrillar plaques. Fibrillar deposits are associated with dystrophic neurites and GFAP-positive astrocytes at ~ 6 months with later microglial activation. |
Progressive impairment between 5–7 and 15–17 months in some tests of cognitive performance, but not others. No change in anxiety levels. |
PS cDKO
Observed
-
Neuronal Loss at 9
Significant increase (about 8-fold) in apoptotic neurons at 2 months of age, although the total number of cortical neurons is not significantly altered due to the low basal level of apoptosis in the cerebral cortex. By 4 months of age, the cumulative loss of cortical neurons reaches about 9 percent of all cortical neurons.
-
Gliosis at 17
Astrogliosis and microgliosis; up-regulation of GFAP and other inflammatory markers are observed in the neocortex and hippocampus at 6 months, and this increases with age (Wines-Samuelson et al., 2010, Beglopoulos et al., 2004).
-
Synaptic Loss at 26
Reduction in synaptophysin immunoreactivity in hippocampal CA1 pyramidal neurons by 6 months. Reduction in dendritic spines by 9 months (Saura et al., 2004).
-
Cognitive Impairment at 9
Deficits in the Morris water maze and contextual fear conditioning are mild at 2 months, but become more severe with age (Saura et al., 2004).
Absent
-
Plaques at
Absent.
-
Tangles at
Tangles are absent, but hyperphosphorylation of tau has been reported in 9 month-old mice.
No Data
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| PSEN1, PSEN2 | PSEN1: Conditional Knock-out; PSEN2: Knock-Out | Alzheimer's Disease | At 2 months the number of apoptotic neurons is elevated about 8-fold. By 6 months, about 18 percent of of cortical neurons are lost. Up-regulation of inflammatory markers and progressive astrogliosis and microgliosis in the neocortex and hippocampus. |
Impairments in hippocampal learning and memory as indicated by Morris water maze and contextual fear conditioning evident by 2 months and worsens with age. |
rTg9191
Observed
-
Neuronal Loss at 9
Expression of the tetracycline transactivator (tTA) resulted in reduced forebrain weight and smaller dentate gyri in rTg9191 mice compared to non-Tg littermates. This effect was also observed in mice expressing tTA alone, and is thought to be a developmental effect, as it was observed even in young mice (e.g., 2-6 months of age).
-
Plaques at 35
Plaques emerge first in the cerebral cortex, starting around 8 months of age. This is followed by plaques in the hippocampus at 10.5 to 12.5 months of age. Some dense core plaques develop.
-
Gliosis at 104
rTg9191 mice develop reactive gliosis (astrocytosis and microgliosis) in the vicinity of dense-core plaques by 24 months of age.
Absent
-
Tangles at
Tangles are not observed, but hyperphosphorylated tau develops with age.
-
Cognitive Impairment at
No transgene-related deficits seen in Morris water maze (4, 12, 21, 24 months of age) or fixed consecutive number test (23 months of age).
No Data
-
Synaptic Loss at
Unknown.
-
Changes in LTP/LTD at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP | APP KM670/671NL (Swedish), APP V717I (London) | APP: Transgenic | Alzheimer's Disease | Age-associated pathology in the cerebral cortex and hippocampus starting at 8 and 10½-12½ months of age, respectively. Gliosis and hyperphosphorylated tau in the vicinity of dense-core plaques. Fibrillar oligomeric species, e.g., Aβ dimers. |
No transgene-related deficits seen in Morris water maze (4, 12, 21, 24, months of age) or fixed consecutive-number (23 months of age) tests. |
rTgTauEC
Observed
-
Neuronal Loss at 83
Neuronal loss is detectable by 24 months of age in areas with transgene expression (e.g. layer II of the EC and parasubiculum), compared with age-matched mice expressing only tTA. Significant neuronal loss was not observed at 21 months (de Calignon et al., 2012).
-
Tangles at 78
By 18 months of age, Gallyas silver-positive staining is observed, indicative of paired helical filaments. This is followed by thioflavin-S staining at 24 months. Tau pathology develops first in neurons of the medial EC expressing human tau, followed by neurons in the dentate gyrus, CA1 and CA2/3(de Calignon et al., 2012).
-
Gliosis at 104
Microglial activation and astrogliosis by 24 months of age, in conjunction with axonal degeneration and neuronal loss (de Calignon et al., 2012).
-
Synaptic Loss at 104
By 24 months of age pre- and post-synaptic densities were reduced in the middle third of the molecular layer of the dentate gyrus as measured by synapsin-1 and PSD-95 staining (de Calignon et al., 2012).
-
Changes in LTP/LTD at 70
At 16 months of age, subtle differences in electrophysiological properties have been observed in the perforant pathway, including a decrease in LTP and an increase in the probability of neurotransmitter release (Polydoro et al., 2014).
-
Cognitive Impairment at 70
Very mild and specific deficits in contextual fear conditioning at 16 months of age, but no deficits in the radial arm maze (Polydoro et al., 2014).
Absent
-
Plaques at
Absent.
No Data
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| MAPT | MAPT P301L | MAPT: Transgenic | Frontotemporal Dementia, Alzheimer's Disease | Propagating tau pathology starting in the entorhinal cortex and spreading to regions functionally connected to the EC (e.g., dentate gyrus). Neurodegeneration and axonal degeneration, first in EC and parasubiculum. Gliosis and synaptic loss. |
Subtle cognitive deficit in contextual fear conditioning, but not in the radial arm maze, at 16 months. Mild specific deficit in locomotor activity in the open field test. |
rTg(tauP301L)4510
Observed
-
Neuronal Loss at 24
Decreased (~60%) CA1 hippocampal neurons by 5.5 months with significant loss in brain weight. Progressive loss of neurons and brain weight in 7 and 8.5 month mice with ~23% of CA1 pyramidal cells remaining at 8.5 months. Gross atrophy of the forebrain by 10 months.
-
Tangles at 17
Pretangles as early as 2.5 months. Argyrophilic tangle-like inclusions in cortex by 4 months and in hippocampus by 5.5 months.
-
Synaptic Loss at 35
Significant loss of dendritic spines at 8-9 months (~30% decrease in spine density in somatosensory cortex).
-
Cognitive Impairment at 11
No significant abnormalities at 1.3 months but retention of spatial memory (Morris Water Maze) became impaired from 2.5 to 4 months. No significant motor impairments up to 6 months. Spatial memory improved when transgene suppressed by dox.
Absent
-
Plaques at
Absent.
No Data
-
Changes in LTP/LTD at
Electrophysiological properties of cortical neurons are altered as early as 1 to 3 months of age. In freely behaving mice, individual neocortical pyramidal neurons are less active as is the neocortical network as a whole. Hyperexcitability of cortical neurons has been observed in vitro, along with effects on resting membrane potential and action potential firing rates.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| MAPT | MAPT P301L | MAPT: Transgenic | Alzheimer's Disease, Frontotemporal Dementia | Argyrophilic tangle-like inclusions in cortex by 4 months and in hippocampus by 5.5 months. Decreased CA1 neurons (~60 percent) by 5.5 months. Gross forebrain atrophy by 10 months. The number of CA1 neurons stabilized after a brief (six to eight week) suppression of transgenic tau. |
No significant abnormalities at 1.3 months in the Morris Water Maze. Spatial memory impairments by 2.5 to 4 months. No significant motor impairment up to 6 months of age. When the transgene was suppressed with dox at 2.5 months, spatial memory improved. |
TAS10 (thy1-APPswe)
Observed
-
Plaques at 52
Fibrillar amyloid plaques develop by 12 months in the cortex and hippocampus.
-
Gliosis at 26
Astrogliosis and microgliosis underway by 6 months of age in the dentate gyrus.
-
Synaptic Loss at 104
TAS10 mice initially have more synapses than non-Tg mice; specifically, greater numbers of synapses per neuron were documented at 12 and 18 months of age. However, by 24 months of age, TAS10 mice have fewer synapses than non-Tg mice.
-
Cognitive Impairment at 26
Deficits in spatial learning present by 6 months of age as measured by the Morris water maze. No difference from non-Tg at 2 months of age. Deficits in Y maze at 12 months. No deficit in fear conditioning up to 24 months of age.
Absent
-
Neuronal Loss at
Qualitative difference in neuronal numbers at 24 months in specific regions of the hippocampus, but no significant neuronal loss.
-
Tangles at
Absent.
-
Changes in LTP/LTD at
At 12 to 14 months of age, deficits in basal synaptic transmission have been observed in the CA1 region, but short- and long-term synaptic plasticity are relatively normal (Brown et al., 2005).
No Data
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP | APP KM670/671NL (Swedish) | APP: Transgenic | Alzheimer's Disease | Age-related accumulation of Aβ in the hippocampus and cortex leading to plaque deposition by 12 months of age. Early gliosis and dystrophic neurites, not limited to the vicinity around plaques. Changes in synaptic morphology and number, along with increased number of lysosomes. |
Deficits in spatial memory prior to Aβ deposition, including deficits in the Morris water maze by 6 months Deficits in spontaneous alternation behavior in the Y maze by 12 months. No deficit in fear conditioning. |
TASTPM (TAS10 x TPM)
Observed
-
Plaques at 26
Aβ begins to deposit at 3 months of age, with fibrillar plaques evident by 6 months in the cerebral cortex and hippocampus. Some vascular amyloid is also observed. Plaque pathology is more severe in female mice.
-
Gliosis at 28
Greater numbers of reactive astrocytes and microglia by 6 months of age in the hippocampus and cortex, predominantly near amyloid plaques.
-
Cognitive Impairment at 26
Age-dependent impairment in object recognition memory starting around 6 months of age for both sexes. No impairment at 3 to 4 months of age.
Absent
-
Neuronal Loss at
Minimal neuronal loss up to 10 months of age. Some signs of loss in the immediate vicinity of plaques in the hippocampus (Howlett et al., 2008).
-
Tangles at
Absent.
No Data
-
Synaptic Loss at
Unknown.
-
Changes in LTP/LTD at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP, PSEN1 | APP KM670/671NL (Swedish), PSEN1 M146V | APP: Transgenic; PSEN1: Transgenic | Alzheimer's Disease | Aβ deposits beginning at 3 months of age, with fibrillar plaques by 6 months in the cerebral cortex and hippocampus. Some vascular amyloid. Plaques surrounded by dystrophic neurites and reactive glia. No tangles or neuronal loss. Female mice have more rapid and severe amyloid pathology. |
Age-dependent impairment in object recognition memory starting around 6 months of age. |
Tau35
Observed
-
Tangles at 35
Abnormally phosphorylated tau detected at two months and by eight months tau was mislocalized and misfolded and dystrophic neurites were observed. Tangle-like structures observed in the hippocampus by 14 months.
-
Synaptic Loss at 61
At 14 months synapsin1 protein levels were decreased but synaptophysin levels remained at wild-type levels.
-
Cognitive Impairment at 36
In the Morris water maze, Tau35 had the same performance as wild-type animals at six months but developed progressive deficits by eight months.
Absent
-
Gliosis at
Gliosis was not observed at 14 months.
No Data
-
Neuronal Loss at
Cell death was not formally assessed, however, overt neuronal death was not seen in the hippocampus.
-
Plaques at
Unknown.
-
Changes in LTP/LTD at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| MAPT | MAPT: Transgenic | Progressive Supranuclear Palsy, Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy | Progressive tau pathology in the hippocampus, including abnormally phosphorylated and misfolded tau, mislocalized tau, and tangle-like structures. Dystrophic neurites. |
Impaired spatial learning and memory in the Morris water maze. Early motor impairments, including abnormal limb clasping, Rotarod deficits and decreased grip strength. |
Tau4RTg2652
Observed
-
Cognitive Impairment at 13
Deficits in spatial learning and memory as indicated by performance in the Barnes maze at multiple time points (3, 6, 11 months of age).
Absent
-
Neuronal Loss at
Absent.
-
Plaques at
Absent.
-
Tangles at
Absence of mature neurofibrillary tangles, but extensive pretangle pathology throughout the brain (e.g. phospho-tau).
No Data
-
Gliosis at
Unknown.
-
Synaptic Loss at
Unknown.
-
Changes in LTP/LTD at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| MAPT | MAPT: Transgenic | Frontotemporal Dementia, Other Tauopathy, Alzheimer's Disease | Extensive pretangle pathology throughout the brain (e.g. phospho- tau) but no mature neurofibrillary tangles and only mild oligomeric tau, restricted to the CA1 region of the hippocampus. Dystrophic neurites and axonal pathology (spheroids). No overt neuronal loss. |
Motor deficits develop with age, including decreased grip strength and impaired Rotarod performance. Cognitive deficits, indicative of impaired spatial learning and memory, as assessed by the Barnes maze. |
Tau609 (Tau 10 + 16)
Observed
-
Neuronal Loss at 65
Significant loss of NeuN-positive neurons in layer II of the entorhinal cortex at 15 months, and in the hippocampal CA1 region at 24 months, compared with non-Tg controls. No difference in the hippocampus at 18 months.
-
Tangles at 65
Gallyas silver-positive intracellular inclusions of hyperphosphorylated tau aggregates in the entorhinal cortex at 15 months, and in the hippocampus and cerebral cortex at 24 months, but not at 18 months.
-
Gliosis at 52
At 12 months of age, Iba1-positive cells are observed. GFAP is observed at 24 months of age.
-
Synaptic Loss at 28
Reduced synaptic density at 6 months of age in select hippocampal areas compared to non-Tg mice and those expressing wild-type human tau. Densities in other areas were comparable until later ages (i.e., 24 months).
-
Changes in LTP/LTD at 26
Some changes in basal synaptic transmission and significant impairment of LTP evident by 6 months of age in some regions of the hippocampus.
-
Cognitive Impairment at 26
Deficits in spatial reference memory by 6 months of age as measured by the Morris water maze. No difference from non-Tg littermates at 4 months of age.
Absent
-
Plaques at
Absent.
No Data
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| MAPT | MAPT IVS10+16 C>T | MAPT: Transgenic | Frontotemporal Dementia, Alzheimer's Disease, Other Tauopathy | Aggregated tau in neurons of the entorhinal cortex, hippocampus, and cerebral cortex at advanced ages. Intraneuronal accumulation of tau oligomers in the hippocampus. Neuronal loss in the entorhinal cortex and hippocampus. Gliosis. Some hippocampal areas affected by age-related synaptic dysfunction and reduced synaptic density. |
Impaired spatial reference memory as measured by the Morris water maze by 6 months of age. |
TauC3 (Transgenic caspase-cleaved tau)
Observed
-
Synaptic Loss at 6
Reduced levels of synaptic proteins as early as 1.3 months, including synaptophysin. Further reductions in 3 and 6-month-old animals.
-
Cognitive Impairment at 6
Learning and memory impairments as early as 1.3 months in several behavioral tests including the Y-maze, passive avoidance, and novel object recognition.
Absent
-
Neuronal Loss at
No significant neurodegeneration by 12 months of age.
-
Plaques at
Amyloid plaques were absent.
-
Tangles at
Neurofibrillary tangles were not observed; however, hyperphosphorylated tau occurred early in the form of oligomers and aggregates.
-
Gliosis at
No significant astrogliosis in the hippocampus or cortex by 12 months of age.
No Data
-
Changes in LTP/LTD at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| MAPT | MAPT: Transgenic | Alzheimer's Disease, Frontotemporal Dementia | No significant cell loss or astrogliosis in the brain. Age-dependent reduction in synaptic proteins (e.g. synaptophysin, PSD95) by 1.3 to 3 months of age. Hyperphosphorylated tau oligomers and aggregates. |
Learning and memory deficits by 1.3 to 3 months of age, as assessed by the Y-maze and passive avoidance tests. No significant motor impairment. |
TauΔK280 ("Proaggregation mutant")
Observed
-
Tangles at 104
Mature tangles are observed only at advanced age (>24 months), but extensive pre-tangle pathology develops with as little as three months of transgene expression. This includes mislocalization of tau to the somatodendritic compartment, conformational changes indicative of aggregation, and hyperphosphorylation (e.g. Ser 262, Ser 356).
-
Synaptic Loss at 57
Electron microscopy showed a moderate decrease in spine synapses in the CA1 region of the hippocampus following 13 months of gene expression.
-
Changes in LTP/LTD at 52
Impaired hippocampal LTP in the CA1 and CA3 areas.
-
Cognitive Impairment at 70
Cognitive deficits in the Morris water maze and in passive-avoidance paradigms.
Absent
-
Neuronal Loss at
Absent.
-
Plaques at
Absent.
No Data
-
Gliosis at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| MAPT | MAPT K280del | MAPT: Transgenic | Alzheimer's Disease, Frontotemporal Dementia | Abundant pre-tangle pathology, but only rare mature tangles, and only at advanced ages. Tau pathology included mislocalization of tau to the somatodendritic compartment, aggregation, and hyperphosphorylation. |
Unknown. |
Tau P301L
Observed
-
Tangles at 35
Hyperphosphorylation, conformational changes, and aggregation of tau resulting in tangle-like pathology by 8 months.
-
Gliosis at 30
Astrogliosis by 7 months.
-
Changes in LTP/LTD at 26
Deficit in LTP in CA1 region of the hippocampus at 6 months, but enhanced LTP in the dentate gyrus at a young age (8-10 weeks).
-
Cognitive Impairment at 22
Age-associated deficit in two cognitive tests that do not depend heavily on motor ability, the passive avoidance task (significant deficit starting at 5 months, but not 2 or 3 months of age) and a novel object recognition task (significant deficit at 9 months, but not at 2, 3, 5, or 7 months of age) (Maurin et al., 2014).
Absent
-
Plaques at
Absent.
No Data
-
Neuronal Loss at
Unknown.
-
Synaptic Loss at
Unknown at advanced age. Young mice (1-2 months) have a significantly higher spine maturation index than controls. At 4-6 months, the spine maturation index remains high in the hippocampus, but is reduced to control levels in the cortex. Note, these results were generated using the progeny of Tau P301L x transgenic Thy1-YFP (Kremer et al., 2011).
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| MAPT | MAPT P301L | MAPT: Transgenic | Alzheimer's Disease, Frontotemporal Dementia | Pathologic hyperphosphorylation and conformational change of parenchymal tau in brain tissues starting at 7 months. Tangle-like pathology is mainly observed in the brain stem and spinal cord, and to a lesser extent in the midbrain and cerebral cortex. Age-dependent increase in total tau in CSF. |
Age-associated deficits in a passive avoidance task (starting at 5 months) and a novel object recognition task (starting at 9 months). At a young age (~2 months) outperforms wild-type littermates in object recognition memory. Progressive motor impairment and reduced activity, accompanied by increased clasping of hind and then forelimbs around seven months. |
Tau P301S (Line PS19)
Observed
-
Neuronal Loss at 39
Neuron loss in the hippocampus and entorhinal cortex by nine to12 months, as well as in the amygdala and neocortex becoming more severe by 12 months (Yoshiyama et al., 2007).
-
Tangles at 23
Neurofibrillary tangles in the neocortex, amygdala, hippocampus, brain stem and spinal cord at six months with progressive accumulation (Yoshiyama et al., 2007).
-
Gliosis at 11
Microgliosis at three months, especially in the white matter of the brain and spinal cord. Increased microgliosis by six months in white and gray matter of the hippocampus, amygdala, entorhinal cortex, and spinal cord. Microglial activation precedes astrogliosis (Yoshiyama et al., 2007).
-
Synaptic Loss at 13
Synaptophysin immunoreactivity decreased progressively from three to six months in the CA3 region of the hippocamus. Impaired synaptic function (Yoshiyama et al., 2007).
-
Changes in LTP/LTD at 26
Reduced LTP in the CA1 region of the hippocampus at six months. Altered basal synaptic transmission (smaller fiber volley amplitude, fEPSP slopes, and amplitudes) (Yoshiyama et al., 2007). Impaired hippocampal LTP as measured in freely moving mice (Lasagna-Reeves, 2016).
-
Cognitive Impairment at 27
Impairments in spatial learning and memory ability in the Morris water maze in six-month-old animals (Takeuchi et al., 2011). Impaired memory in assays of contextual fear conditioning (Lasagna-Reeves 2016).
Absent
-
Plaques at
Absent.
No Data
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| MAPT | MAPT P301S | MAPT: Transgenic | Alzheimer's Disease, Frontotemporal Dementia | Neuron loss and brain atrophy by eight to 12 months, especially in the hippocampus and spreading to the neocortex and entorhinal cortex. Neurofibrillary tangles in the neocortex, amygdala, hippocampus, brain stem, and spinal cord. Neuroinflammation with microgliosis and astrocytosis. |
Impairments in spatial memory and learning ability in Morris water maze. Paralysis at seven to 10 months associated with a hunched-back posture followed by feeding difficulties. About 80 percent mortality by 12 months with median survival of about nine months. |
TauPS2APP
Observed
-
Plaques at 17
Rare amyloid plaques at 4 months, plaques become more abundant with age. By 8 months the number of amyloid plaques increases considerably in the subiculum and the CA1 region of the hippocampus (Grueninger et al., 2010).
-
Tangles at 70
Abnormally phosphorylated tau is detectable at 4 months in both TauPS2APP and tau single transgenic mice especially in the subiculum, amygdala, and the CA1 region of the hippocampus. Tau pathology increases with age with numerous tangle-like deposits in the hippocampus confirmed by Gallyas silver staining at 16 months (Grueninger et al., 2010).
-
Cognitive Impairment at 17
Impairment is not age-associated and does not progress from age 4 months to 12 months (Grueninger et al., 2010).
Absent
-
Neuronal Loss at
No overt neuronal loss in the hippocampus at 16 months (Grueninger et al., 2010).
No Data
-
Gliosis at
Unknown.
-
Synaptic Loss at
Unknown.
-
Changes in LTP/LTD at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP, MAPT, PSEN2 | APP KM670/671NL (Swedish), MAPT P301L, PSEN2 N141I (Volga German) | APP: Transgenic; MAPT: Transgenic; PSEN2: Transgenic | Alzheimer's Disease | Phosphorylated tau accumulation in the subiculum and the CA1 region of the hippocampus at 4 months. Neurofibrillary tangles in these regions as well as the amygdala. Amyloid plaques. Dystrophic neurites and neuropil threads containing abnormally phosphorylated tau. No overt neuronal loss. |
Impaired spatial learning in the Morris water maze at 4 months but impairment is not progressive between 4 and 12 months and appears to be independent of pathology. |
Tau R406W transgenic
Observed
-
Tangles at 78
Congophilic tau inclusions in a subset of forebrain neurons around 18 months of age. Detected by Congo red, thioflavin S, and Gallyas silver stain.
-
Cognitive Impairment at 70
Impairments in the contextual and cued fear conditioning test at 16–23 months compared with wild-type littermates. No detectable sensorimotor deficits.
Absent
-
Plaques at
Absent.
No Data
-
Neuronal Loss at
Unknown.
-
Gliosis at
Unknown.
-
Synaptic Loss at
Unknown.
-
Changes in LTP/LTD at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| MAPT | MAPT R406W | MAPT: Transgenic | Frontotemporal Dementia, Alzheimer's Disease | Argyrophilic and congophilic tau inclusions in neurons of the forebrain with age. Detectable with Congo red, thioflavin-S and Gallyas silver stain. Congophilic tau inclusions also in the hippocampus and amygdala. Mainly straight tau filaments. |
Impairments in contextual and cued fear conditioning at 16–23 months compared with wild-type littermates. No detectable sensorimotor deficits. |
TauRDΔK280 (“Proaggregation mutant”)
Observed
-
Neuronal Loss at 22
Neuronal loss in the dentate gyrus (granule neurons) following 5 months of transgene expression. Shrinkage of the molecular layer of the hippocampus.
-
Tangles at 9
Tau tangles and aggregates with as little as 2-3 months of transgene expression. Tangles start in the entorhinal cortex and amygdala and spread to the neocortex by 15 months. Heterogeneous tangle morphology, including flame-shaped.
-
Gliosis at 91
Astrogliosis in the hilus region of the hippocampus after 21 months of transgene expression. Additional increases in GFAP-positive astrocytes in the entorhinal and piriform cortices.
-
Synaptic Loss at 41
Hippocampal synaptic loss as indicated by multiple measures following 9.5 months of transgene expression. Reduced synaptophysin immunoreactivity and reduced number of spine synapses as measured by electron microscopy.
-
Changes in LTP/LTD at 43
Multiple deficits in synaptic plasticity, including deficits in LTP and LTD, after 10 months of transgene expression. Functional changes are associated with structural synaptic changes, local calcium dysregulation, and a decrease in the synaptic vesicle pool.
-
Cognitive Impairment at 43
Learning and memory impairments are apparent after 10 months of transgene expression as assessed by the Morris water maze and passive avoidance tasks.
Absent
-
Plaques at
Absent.
No Data
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| MAPT | MAPT K280del | MAPT: Transgenic | Alzheimer's Disease, Frontotemporal Dementia | Tau aggregates and tangles as early as 2-3 months after gene expression. Gallyas silver-positive neurons abundant in the entorhinal cortex and amygdala, spreading to the neocortex by 15 months. “Ballooned” neurons. Astrogliosis. Synaptic structural changes and reduced synaptic number. Hippocampal neuronal loss. |
Reversible learning and memory deficits in the Morris water maze and passive avoidance test. No significant motor deficit, although slight reduction in Rotarod performance. |
Tau V337M
Observed
-
Neuronal Loss at 43
Evidence of hippocampal neuronal degeneration in 10 month old animals: irregularly shaped neurons with tau pathology that stained with propidium iodide. As characteristics of apoptosis were not observed, the neurons were thought to be undergoing non-apoptotic atrophic degeneration (Tanemura et al., 2002).
-
Tangles at 48
Fibrillar staining in the hippocampus of 11 month old animals by Congo red birefringence. Absent in 4 month old mice, indicating the formation of these neurofilament-like structures occurs between 4 and 11 months (Tanemura et al., 2001).
-
Changes in LTP/LTD at 65
In hippocampal slices there was an attenuation of the amplitude of Schaffer collateral evoked hippocampal depolarization (Tanemura et al., 2002).
-
Cognitive Impairment at 48
Behavioral abnormalities measured in 11 month-old mice. They spent more time in the open arms of the elevated plus maze and had greater overall locomoter activity. No differences in the Morris water maze compared with non-transgenic mice, suggesting the transgenic animals retain spatial recognition abilities (Tanemura et al., 2002).
Absent
-
Plaques at
Absent.
No Data
-
Gliosis at
Unknown.
-
Synaptic Loss at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| MAPT | MAPT V337M (Seattle Family A) | MAPT: Transgenic | Alzheimer's Disease, Frontotemporal Dementia | SDS-insoluble tau aggregates in hippocampus. Degenerating neurons in the hippocampus containing phosphorylated and ubiquitinated tau aggregates with β-sheet structure. |
Higher overall spontaneous locomotion than non-transgenic littermates in elevated plus maze. No differences in the Morris water maze. |
TBA42
Observed
-
Neuronal Loss at 52
Age-dependent neuronal loss in the CA1 region of the hippocampus. No difference from wild-type mice at 3 and 6 months of age, but approximately 35% loss at 12 months of age.
-
Plaques at 52
Very rare extracellular Aβ deposits.
-
Gliosis at 52
Marked gliosis in the hippocampus as measured by GFAP staining at 12 months.
-
Cognitive Impairment at 54
Age-dependent deficits in working and spatial reference memory at 12 months, but not at 3 and 6 months.
Absent
-
Tangles at
Absent.
No Data
-
Synaptic Loss at
Unknown.
-
Changes in LTP/LTD at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP | APP: Transgenic | Alzheimer's Disease | Intraneuronal accumulation of Aβ peptides in the hippocampus by 3 months and in cerebellar nuclei by 6 months. Marked gliosis in the hippocampus by 12 months. Very rare extracellular Aβ deposits. |
Age-dependent behavioral deficits, including working memory as assessed by the cross maze at 12 months, but not at 3 or 6 months. Early and persistent decrease in anxiety in the elevated plus maze. Comparable to wild-type in general motor coordination at 3 and 6 months as indicated by the balance-beam test, but impairment at 12 months. |
Tg2576
Observed
-
Plaques at 48
Numerous parenchymal Aβ plaques by 11-13 months.
-
Gliosis at 43
Increase in microglial density and size in plaque-forming areas of the brain including the hippocampus, frontal cortex, entorhinal cortex, and occipital cortex in 10-16 month old hemizygotes (Frautschy et al., 1998).
-
Synaptic Loss at 20
Dendritic spine loss by 4.5 months In the CA1 region of the hippocampus (Lanz et al., 2003).
-
Changes in LTP/LTD at 22
By 5 months, there was a decline in LTP in the dentate gyrus after perforant path stimulation compared to wild-type; impairment was not observed at 2 months (Jacobsen et al., 2006). Both the CA1 and dentate gyrus of aged mice (>15 months) are impaired (Chapman et al., 1999). Differences have been observed between the Schaffer collateral and mossy fiber pathways (Jung et al., 2011).
-
Cognitive Impairment at 26
Impaired spatial learning, working memory, and contextual fear conditioning at <6 months although other studies have reported normal cognition at this age with progressive impairment by >12 months.
Absent
-
Neuronal Loss at
Absent or very limited.
-
Tangles at
Absent.
No Data
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP | APP KM670/671NL (Swedish) | APP: Transgenic | Alzheimer's Disease | Numerous parenchymal Aβ plaques by 11-13 months with some vascular amyloid. Oxidative lipid damage, astrogliosis and microgliosis. No tangles or neuronal loss. |
Impaired spatial learning, working memory, and contextual fear conditioning reported at <6 months although other studies have reported normal cognition at this age with progressive impairment by >12 months. |
Tg2576/Tau(P301L) (APPSwe-Tau)
Observed
-
Plaques at 39
Plaques develop gradually with age. No plaques at 5 months. Very few small plaques at 6 and 7 months. By 9 months plaques scattered throughout the cortex, hippocampus and amygdala, continue to increase at 12 months. Similar distribution as Tg2576.
-
Tangles at 13
Neurofibrillary tangles in the spinal cord and pons as early as 3 months, but more consistent and numerous by 6 months. Tangles morphologically similar to those in JNPL3 mice but older bigenic female mice had a marked increase in neurofibrillary tangles in limbic areas by 6 months, especially the olfactory cortex, entorhinal cortex and amygdala (Lewis et al., 2001).
-
Gliosis at 13
Reactive astrocytes and microglia as early as 3 months in the hippocampus as measured by GFAP and CD45. Increased astrocytosis with age especially in limbic areas with the most neurofibrillary tangles. Microglia especially concentrated around plaques at 9 and 12 months (Lewis et al., 2001).
Absent
No Data
-
Synaptic Loss at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP, MAPT | APP KM670/671NL (Swedish), MAPT P301L | APP; MAPT: Transgenic | Alzheimer's Disease | Gradual appearance of plaques; by 9 months plaques are scattered throughout the cortex, hippocampus, and amygdala similar to Tg2576. Tau pathology more extensive than JNPL3. Astrocytosis and microgliosis. |
Motor disturbances similar to JNPL3, with identical range in age of onset. Reduced vocalization and decreased grooming. |
Tg4-42
Observed
-
Neuronal Loss at 35
Age- and dose-dependent neuronal loss in the hippocampus CA1 region of hemizygous and homozygous mice. Compared with wild-type, hemizygous mice had 38% neuronal loss at 8 months, and 49% loss at 12 months. No difference at 3 months.
-
Gliosis at 9
Reactive microglia and astrocytes in the hippocampus starting at 2 months.
-
Synaptic Loss at 37
Altered synaptophysin staining in the CA3 region of the hippocampus. More pronounced in homozygous mice than hemizygous mice at 8 months.
-
Cognitive Impairment at 35
Spatial reference memory is impaired as assessed by Morris water maze at 8 months in homozygous mice and 12 months in hemizygous mice. Deficit is age-dependent and is not detected at 3 months. Impaired contextual fear conditioning at 12 months.
Absent
-
Plaques at
Absent.
-
Tangles at
Absent.
No Data
-
Changes in LTP/LTD at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP | APP: Transgenic | Alzheimer's Disease | Aβ4-42 is dectable starting at two months, predominantly in the CA1 region of the hippocampus, but also in the occipital cortex, piriform cortex, striatum, and superior colliculus. Age- and dose-dependent hippocampal neuronal loss is seen in the CA1 region as well as microgliosis and astrogliosis. |
Age-dependent spatial learning deficit as demonstrated in the Morris water maze, specifically, the absence of a preference for the target quadrant starting at eight months in homozygous mice and at 12 months in hemizygous mice. Impaired contextual fear conditioning. |
Tg-ArcSwe
Observed
-
Plaques at 22
Extracellular amyloid plaque deposition starts at around 5-6 months of age (Lord et al., 2006) and is most consistently present in the cerebral cortex, hippocampus, and thalamus (Lillehaug et al., 2013).
-
Gliosis at 26
Microgliosis and astrogliosis most prominent in the hippocampus, but also locally around deposits in the cerebral cortex and thalamus.
-
Cognitive Impairment at 17
Transgene-dependent spatial learning impairment in the Morris water maze (4-8 months) (Lord et al., 2009) and in an Intellicage-based Passive Avoidance test (16 months)(Codita et al., 2010).
Absent
-
Neuronal Loss at
Absent.
-
Tangles at
Absent.
No Data
-
Synaptic Loss at
Unknown.
-
Changes in LTP/LTD at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP | APP KM670/671NL (Swedish), APP E693G (Arctic) | APP: Transgenic | Alzheimer's Disease, Cerebral Amyloid Angiopathy | Strong intraneuronal Aβ aggregation starting at 1 month and increasing with age. Extracellular amyloid plaque at 5-6 months, most consistent in the cerebral cortex, hippocampus, and thalamus. Congophilic parenchymal plaques are predominant, but some mice show marked CAA, particularly in the thalamus. |
Mild spatial learning deficits at 4-8 months in Morris water maze and impaired functioning in a passive avoidance test at 16 months. |
TgCRND8
Observed
-
Neuronal Loss at 26
Variable cell loss by region. No difference in overall cell count, but fewer hippocampal neurons at 6 months (Brautigam et al., 2012).
-
Plaques at 13
Amyloid deposition progresses with age. Thioflavin S-positive amyloid deposits at 3 months; dense cored plaques and neuritic pathology by 5 months. Plaques appear first in the subiculum, amygdala and frontal cortex, spread to the dentate gyrus, the olfactory bulb, and later thalamus, cerebral vasculature, and striatum, followed by the cerebellum and brain stem (Chishti et al., 2001).
-
Gliosis at 13
Microglia activation appears simultaneously with Aβ deposition, with only rare activated microglia at 9-10 weeks, but by 13-14 weeks microglia cluster around Aβ deposits in the cerebral cortex and hippocampus; numerous by 20 weeks. Robust astrogliosis slightly later with clusters of GFAP+ astrocytes emerging around plaques at 13-14 weeks (Dudal et al., 2004).
-
Synaptic Loss at 26
Reduced synaptophysin immunoreactivity in the vicinity of plaques at 6 months (Adalbert et al., 2009).
-
Changes in LTP/LTD at 26
In hippocampal slices from 6- to 12-month-old mice basal excitatory synaptic transmission (as assessed by I/O relationships) and LTP at CA1 are reduced in TgCRND8 mice compared with wild-type mice (Kimura et al., 2012).
-
Cognitive Impairment at 13
Early impairment in acquisition and learning reversal in the reference memory version of the Morris water maze, present by 3 months (Chishti et al., 2001).
Absent
-
Tangles at
Neurofibrillary tangles are absent (Chishti et al., 2001). Tau is hyperphosphorylated, nitrosylated and aggregated at 7-12 months especially in the neocortex, dentate gyrus, and the CA1 and CA3 areas of the hippocampus (Bellucci et al., 2007).
No Data
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP | APP KM670/671NL (Swedish), APP V717F (Indiana) | APP: Transgenic | Alzheimer's Disease | Rapid, early plaque development, with thioflavin S-positive amyloid deposits at 3 months; dense cored plaques and neuritic pathology by 5 months. Plaques become more extensive with age. More Aβ42 than Aβ40. Activated microglia appear concurrently with plaques, whereas GFAP+ astrocytes follow later, about 13-14 weeks. Dystrophic neurites at 5 months . |
Early impairment in acquisition and learning reversal in the reference memory version of the Morris water maze by 3 months. Cognitive deficits in the step-down inhibitory avoidance test at 7 months but not at 2 months. Similar to wild-type in motility, exploratory activity, or neuromuscular function at 7 months as evaluated by the rotarod, hole board and grip strength tests. |
Tg-SwDI (APP-Swedish,Dutch,Iowa)
Observed
-
Plaques at 13
Hemizygotes progressively accumulate insoluble Aβ40 and Aβ42, especially within brain microvessels starting at 3 months. Amyloid-β deposits in the subiculum, hippocampus, and cortex at ~3 months. By ~6 months deposits become more numerous and appear in the olfactory bulb and thalamic region as well, with deposits throughout most of the forebrain by 12 months (Davis et al., 2004).
-
Gliosis at 26
Pronounced increase in the number of GFAP-positive astrocytes and activated microglia with age (6-24 months) especially in the thalamus and subiculum and to a lesser extent in the cortex (Miao et al., 2005).
-
Cognitive Impairment at 13
Impaired learning and memory in the Barnes maze task at 3, 9, and 12 months; beginning at 3 months took longer to find the escape hole. No difference in mobility, strength or coordination (Xu et al., 2007).
Absent
-
Tangles at
Absent.
No Data
-
Neuronal Loss at
Unknown.
-
Synaptic Loss at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP | APP KM670/671NL (Swedish), APP E693Q (Dutch), APP D694N (Iowa) | APP: Transgenic | Alzheimer's Disease, Cerebral Amyloid Angiopathy, Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch type | Hemizygotes progressively accumulate insoluble Aβ40 and Aβ42, especially within brain microvessels starting at 3 months. Fibrillar Aβ in micovessels around 6 months. Diffuse plaque-like deposits around 3 months in the subiculum, hippocampus and cortex. Aβ deposits throughout the forebrain by 12 months. |
Impaired learning and memory in the Barnes maze task at 3, 9, and 12 months. Beginning at 3 months transgenic mice took longer to find the escape hole. No difference in mobility, strength or coordination. |
Tg-Swe
Observed
-
Plaques at 52
Plaques are detectable at approximately 12 months and are heterogeneous in morphological structure and size, as well as in terms of fluorescence emitted when stained with luminescent polymers (conformational amyloid ligands)(Philipsson et al., 2009).
-
Gliosis at 52
Microgliosis and astrogliosis are most prominent in the hippocampus, but also found locally around deposits in the cerebral cortex and in thalamus at approximately 12 months (Philipsson et al., 2009).
Absent
-
Neuronal Loss at
Absent.
-
Tangles at
Absent.
No Data
-
Synaptic Loss at
Unknown.
-
Changes in LTP/LTD at
Unknown.
-
Cognitive Impairment at
Unknown.
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| APP | APP KM670/671NL (Swedish) | APP: Transgenic | Alzheimer's Disease | Extracellular amyloid deposition begins at ~12 months. Intraneuronal Aβ aggregates at ~6 months. Extracellular pathology, both cerebrovascular amyloid angiopathy (CAA) and congophilic parenchymal plaques, mainly found in the cerebral cortex, hippocampus and thalamus. Aβ-burden in cerebral cortex is approximately 1.0% (at 12 months) and 2.8% (at 18 months). |
Unknown. |
THY-Tau22
Observed
-
Neuronal Loss at 52
Loss of cells in the CA1 region of the hippocampus from 12 months as measured by DAPI staining and Nissl/cresyl-violet (Schindowski et al., 2006). Also, a significant reduction in the number of choline acetyltransferase (ChAT)-immunopositive cholinergic neurons in the medial septum has been reported (Belarbi et al., 2011).
-
Tangles at 13
Heterozygous animals develop tau pathology starting at 3-6 months. Pathology becomes more severe and widespread with age. Neurofibrillary tangle-like inclusions occur (Gallyas and MC1+) along with rare ghost tangles and paired helical filament-like structures (Schindowski et al., 2006).
-
Gliosis at 13
Age-dependent increase in the number of GFAP+ astrocytes in the hippocampus (hilus, CA1, CA3), cerebral cortex, corpus callosum (Schindowski et al., 2006).
-
Changes in LTP/LTD at 39
Altered paired pulse facilitation (PPF), a form of presynaptic short-term plasticity in 9-10 month old heterozygous animals: PPF increased at 10 ms. Also at this age, impaired maintenance of long term depression as compared with wild-type littermates (Van der Jeugd et al., 2011). Deficit in basal synaptic transmission in the hippocampus, but normal LTP (Schindowski et al., 2006).
-
Cognitive Impairment at 26
Non-spatial memory affected as early as 6 months; spatial memory impaired only after 9 months (Van der Jeugd et al., 2013). Impaired appetitive responding (Lo et al., 2013).
Absent
-
Plaques at
Absent.
No Data
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| MAPT | MAPT G272V, MAPT P301S | MAPT: Transgenic | Frontotemporal Dementia, Alzheimer's Disease | A variety of tau pathologies starting at 3 months, including neurofibrillary tangle-like inclusions, rare ghost tangles, and paired helical filament-like structures. Hyperphosphorylation of tau on many epitopes (e.g. AT8, AT100, AT180, AT270, 12E8, tau-pSer396, and AP422) and mild astrogliosis. |
Increased anxiety and delayed learning from 3 months, and reduced spatial memory at 10 months. No changes in overall motor activity and no gross motor deficits. Increased depression-like and aggressive behavior, co-occurring with disturbances in nocturnal activity. |
TMHT (Thy-1 mutated human tau)
Observed
-
Tangles at 17
Tangles at 4 months and progress with age.
-
Cognitive Impairment at 22
Cognitive impairment by 5 months as measured by the Morris Water Maze.
Absent
-
Plaques at
Absent.
No Data
| Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
|---|---|---|---|---|---|
| MAPT | MAPT V337M (Seattle Family A), MAPT R406W | MAPT: Transgenic | Alzheimer's Disease | Increased total tau, and phosphorylated tau (Thr181, Ser199, Thr231) in amygdala and hippocampus starting at 3 months. |
Spatial memory deficits starting at 5 months (Morris water maze). Olfactory deficits at 5 months (Buried food test). No motor deficits (rota rod, beam walk) or depressive behavior (forced swim test). |