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272 Models
220 Visualizations
AD-related Research Models
Phenotypes Examined
- Plaques
- Tangles
- Neuronal Loss
- Gliosis
- Synaptic Loss
- Changes in LTP/LTD
- Cognitive Impairment
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 (B6SJL)
Observed
-
Plaques at 8
Extracellular amyloid deposition begins around 2 months, first in the subiculum and layer V of the cortex. Aβ42 also accumulates intraneuronally in an aggregated form within the soma and neurites starting at 1.5 months.
-
Neuronal Loss at 24
Neuron loss in cortical layer V and subiculum.
-
Gliosis at 8
Gliosis begins at 2 months.
-
Synaptic Loss at 16
Levels of the presynaptic marker synaptophysin begin to decline by 4 months; levels of syntaxin, another presynaptic marker, and PSD-95, a postsynaptic marker, decline by 9 months
-
Changes in LTP/LTD at 24
Basal synaptic transmission and LTP in hippocampal area CA1 begin to deteriorate between 4 and 6 months
-
Cognitive Impairment at 18
Impaired spatial working memory in the Y-maze test and impaired remote memory stabilization in a contextual-fear-conditioning test by 4 to 5 months of age.
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. |
5xFAD (C57BL6)
Observed
-
Plaques at 8
Amyloid plaques observed in hippocampus, cortex, thalamus, and spinal cord.
-
Neuronal Loss at 52
Approximate 40 percent loss of layer V pyramidal neurons at one year.
-
Gliosis at 8
Microgliosis and astrogliosis are associated with amyloid plaques; microgliosis is associated with vascular damage.
-
Synaptic Loss at 24
Spine density was reduced in pyramidal neurons in somatosensory and prefrontal cortices, but not in the hippocampi, of 5xFAD mice crossed with mice expressing yellow fluorescent protein (YFP mice), compared with mice expressing YFP alone.
-
Changes in LTP/LTD at 8
While spike-timing-dependent long-term potentiation was induced in layer V neurons from wild-type mice, the same stimulation protocol induced long-term depression in neurons from 5xFAD mice.
-
Cognitive Impairment at 24
Impairments of spatial working memory and reduced anxiety emerge between 3 and 6 months and worsen with age.
Absent
No Data
-
Tangles at
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 V. |
Age-dependent memory deficits, motor phenotype, and reduced anxiety. |
A7 APP transgenic
Observed
-
Plaques at 39
These mice develop progressive amyloid deposition in the cerebral cortex by 9-12 months. By 21 months of age amyloid pathology is extensive.
Absent
No Data
-
Tangles at
No data.
-
Neuronal Loss at
No data.
-
Gliosis at
No data.
-
Synaptic Loss at
No data.
-
Changes in LTP/LTD at
No data.
-
Cognitive Impairment at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
APP | APP KM670/671NL (Swedish), APP T714I (Austrian) | APP: Transgenic | Alzheimer's Disease | Progressive amyloid deposition in the cerebral cortex by approximately 9-12 months. |
Unknown. |
AAV-AD
Observed
-
Plaques at 128
Amyloid plaques and cerebral amyloid angiopathy observed 30 months post-injection.
-
Changes in LTP/LTD at 40
Deficits in LTP as Schaffer collateral-CA1 synapse at 10 months (8 months post-injection). LTD similar to controls.
-
Cognitive Impairment at 40
AAV-AD spent less time in the target quadrant of the Morris water maze in probe tests administered 3 and 5 days after training.
Absent
-
Gliosis at
No astrogliosis observed up to 30 months post-injection.
No Data
-
Tangles at
Immunostaining with monoclonal antibodies AT8 and AT100 suggests the presence of (pre)tangle-like structures 30 months post-injection.
-
Neuronal Loss at
No data.
-
Synaptic Loss at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
APP, PSEN1 | APP KM670/671NL (Swedish), APP V717I (London), PSEN1 M146L (A>C) | APP: Virus; PSEN1: Virus | Alzheimer's Disease | Amyloid plaques and cerebral amyloid angiopathy observed 30 months post-injection. Anti-phospho-tau immunostaining suggests the presence of (pre)tangle-like structures. No astrogliosis seen up to 30 months post-injection. |
Compared with control rats at 8 months post-injection, AAV-AD spent less time in the target quadrant of the Morris water maze in probe tests administered 3 and 5 days after training and less time in the center of the open field. |
AAV-GFP-(GA)50
Observed
-
Motor Impairment at 24
Deficits in tail-suspension and rotarod tests, seen at 6 months.
-
Cortical Neuron Loss at 24
At 6 months, neuron loss observed in cortex, including layer V of motor cortex.
-
Cytoplasmic Inclusions at 5
Neuronal poly(GA)- and ubiquitin-positive inclusions already present at 4-6 weeks; rare TDP-43-positive inclusions.
-
Body Weight at 24
Decreased body weight in males, but not females, seen at 6 months.
-
Gliosis at 24
Astrogliosis, but not microgliosis, in cortex and hippocampus, seen at 6 months.
Absent
No Data
-
Lower Motor Neuron Loss at
No data.
-
NMJ Abnormalities at
No data.
-
Muscle Atrophy at
No data.
-
Premature Death at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
Amyotrophic Lateral Sclerosis, Frontotemporal Dementia | Poly(GA)- and ubiquitin-positive inclusions in neurons are primarily cytoplasmic and also co-localize with HR23A and HR23B proteins and the nuclear pore complex proteins RanGAP1 and Pom121. Neuron loss and astrogliosis in cortex and hippocampus. |
Motor deficits, impaired coordination, hyperactivity, increased anxiety, and deficits in contextual and cued fear conditioning. |
AAV-GFP–(GR)100
Observed
-
Motor Impairment at 12
Progressive motor deficits, seen in open-field, rotarod, rod-walk, and wire-hang tests.
-
Cortical Neuron Loss at 6
Fewer cortical neurons than controls, observed as early as 6 weeks of age.
-
Cytoplasmic Inclusions at 24
Very rare TDP-43 inclusions, observed at 6 months.
-
Gliosis at 6
Astrogliosis and microgliosis in cortex and hippocampus, observed at 6 weeks.
Absent
-
Lower Motor Neuron Loss at
Not observed up to 6 months of age.
-
Body Weight at
Normal at 6 months of age.
No Data
-
NMJ Abnormalities at
No data.
-
Muscle Atrophy at
No data.
-
Premature Death at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
Amyotrophic Lateral Sclerosis, Frontotemporal Dementia | Progressive neuron loss in cortex and hippocampus, gliosis. Lacks poly(GR) inclusions. Rare TDP-43 inclusions. |
Progressive motor deficits and age-dependent cognitive impairment. |
Abca7*A1527G/APOE4/Trem2*R47H
Observed
Absent
No Data
-
Plaques at
No data.
-
Tangles at
No data.
-
Neuronal Loss at
No data.
-
Gliosis at
No data.
-
Synaptic Loss at
No data.
-
Changes in LTP/LTD at
No data.
-
Cognitive Impairment at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
Abca7, APOE, Trem2 | TREM2 R47H | Abca7: Knock-In; APOE: Knock-In; Trem2: Knock-In | Alzheimer's Disease | Unknown. |
Unknown. |
Abca7 KO/APOE4/Trem2*R47H
Observed
Absent
No Data
-
Plaques at
No data.
-
Tangles at
No data.
-
Neuronal Loss at
No data.
-
Gliosis at
No data.
-
Synaptic Loss at
No data.
-
Changes in LTP/LTD at
No data.
-
Cognitive Impairment at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
Abca7, APOE, Trem2 | TREM2 R47H | Abca7: Knock-Out; APOE: Knock-In; Trem2: Knock-In | Alzheimer's Disease | Unknown. |
Unknown. |
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
-
Tangles at
Absent.
-
Neuronal Loss 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. |
AD-BXD
Observed
-
Plaques at 24
Transgenic AD-BXD mice develop amyloid plaques by 6 months of age, the earliest age examined. The extent of plaque deposition is strain-dependent.
-
Gliosis at 25
Strain-dependent gliosis by 6 months.
-
Cognitive Impairment at 60
In the AD-BXD population as a whole, transgenic mice performed similarly to non-transgenic littermates in a contextual fear-conditioning test at 6 months, but were impaired at 14 months. The age of onset and severity of impairment are strain-dependent.
Absent
No Data
-
Tangles at
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 | APP KM670/671NL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V | APP: Transgenic; PSEN1: Transgenic | Alzheimer's Disease | Transgenic AD-BXD mice develop amyloid plaques by 6 months of age, although the extent of plaque deposition is strain-dependent. |
Transgenic AD-BXD mice exhibit cognitive deficits, assessed using contextual fear conditioning. The age of onset and severity of impairment are strain-dependent. |
APOE2 Knock-In, floxed (CureAlz)
Observed
Absent
No Data
-
Plaques at
No data.
-
Tangles at
No data.
-
Neuronal Loss at
No data.
-
Gliosis at
No data.
-
Synaptic Loss at
No data.
-
Changes in LTP/LTD at
No data.
-
Cognitive Impairment at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
APOE | APOE: Knock-In | Alzheimer's Disease | Unknown. |
Unknown. |
APOE2 Knock-In (JAX)
Observed
Absent
No Data
-
Plaques at
No data.
-
Tangles at
No data.
-
Neuronal Loss at
No data.
-
Gliosis at
No data.
-
Synaptic Loss at
No data.
-
Changes in LTP/LTD at
No data.
-
Cognitive Impairment at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
APOE | APOE: Knock-In | Alzheimer's Disease | Unknown. |
Unknown. |
APOE2 Targeted Replacement
Observed
Absent
No Data
-
Plaques at
No data.
-
Tangles at
No data.
-
Neuronal Loss at
No data.
-
Gliosis at
No data.
-
Synaptic Loss at
No data.
-
Changes in LTP/LTD at
No data.
-
Cognitive Impairment at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
APOE | APOE: Knock-In | Alzheimer's Disease | Unknown. |
Unknown. |
APOE3 Knock-In, floxed (CureAlz)
Observed
Absent
No Data
-
Plaques at
No data.
-
Tangles at
No data.
-
Neuronal Loss at
No data.
-
Gliosis at
No data.
-
Synaptic Loss at
No data.
-
Changes in LTP/LTD at
No data.
-
Cognitive Impairment at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
APOE | APOE: Knock-In | Alzheimer's Disease | Unknown. |
Unknown. |
APOE3 Knock-In (JAX)
Observed
Absent
No Data
-
Plaques at
No data.
-
Tangles at
No data.
-
Neuronal Loss at
No data.
-
Gliosis at
No data.
-
Synaptic Loss at
No data.
-
Changes in LTP/LTD at
No data.
-
Cognitive Impairment at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
APOE | APOE: Knock-In | Alzheimer's Disease | No data. |
No data. |
APOE3 Knock-In (Lamb)
Observed
Absent
No Data
-
Plaques at
No data.
-
Tangles at
No data.
-
Neuronal Loss at
No data.
-
Gliosis at
No data.
-
Synaptic Loss at
No data.
-
Changes in LTP/LTD at
No data.
-
Cognitive Impairment at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
APOE | APOE: Knock-In | Alzheimer's Disease, Traumatic Brain Injury | Unknown. |
Unknown. |
APOE3 Targeted Replacement
Observed
Absent
No Data
-
Plaques at
No data.
-
Tangles at
No data.
-
Neuronal Loss at
No data.
-
Gliosis at
No data.
-
Synaptic Loss at
No data.
-
Changes in LTP/LTD at
No data.
-
Cognitive Impairment at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
APOE | APOE: Knock-In | Alzheimer's Disease | Unknown. |
Unknown. |
APOE4 Knock-In, floxed (CureAlz)
Observed
Absent
No Data
-
Plaques at
No data.
-
Tangles at
No data.
-
Neuronal Loss at
No data.
-
Gliosis at
No data.
-
Synaptic Loss at
No data.
-
Changes in LTP/LTD at
No data.
-
Cognitive Impairment at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
APOE | APOE: Knock-In | Alzheimer's Disease | Unknown. |
Unknown. |
APOE4 Knock-In (JAX)
Observed
Absent
-
Cognitive Impairment at
At 2 and 12 months of age, APOE4 KI mice perform similarly to wild-type mice in tests of locomotor activity, motor coordination, and working memory.
No Data
-
Plaques at
No data.
-
Tangles at
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 |
---|---|---|---|---|---|
APOE | APOE: Knock-In | Alzheimer's Disease | No data. |
No data. |
APP21
Observed
-
Neuronal Loss at 76
Necrotic neurons in hippocampus and cortex of female rats.
-
Gliosis at 64
Activated (MHCII-positive) microglia present in white matter tracts at 15 months.
-
Cognitive Impairment at 12
Male rats show deficits in Morris water maze as early as 3 months of age. Females show deficits in Barnes maze at 14 months of age.
Absent
-
Plaques at
Do not spontaneously develop amyloid pathology, but can serve as hosts for exogenously seeded amyloid deposits.
No Data
-
Tangles at
“Flame-shaped” profiles in hippocampal neurons of 18- to 19-month-old female rats revealed by hematoxylin-and-eosin-staining.
-
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 V717F (Indiana) | APP: Transgenic | Alzheimer's Disease | No plaques to 30 months of age. Necrotic neurons in hippocampus and cortex by 19 months, in females; neuron loss not observed in cortices of 19-month males. |
Male rats show deficits in Morris water maze as early as 3 months of age. Females show deficits in Barnes maze at 14 months of age. |
APP23
Observed
-
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).
-
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).
-
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
-
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).
-
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).
-
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 knock-in (humanized Aβ)
Observed
Absent
-
Plaques at
None observed at 3 months.
-
Tangles at
None observed at 3 months.
-
Neuronal Loss at
None observed at 3 months.
No Data
-
Gliosis at
No data.
-
Synaptic Loss at
No data.
-
Changes in LTP/LTD at
No data.
-
Cognitive Impairment at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
App | App: Knock-In | Alzheimer's Disease | No plaques, neurofibrillary tangles, or neuron loss observed at three months, the oldest age reported. |
Unknown. |
App knock-in (humanized Aβ)
Observed
Absent
No Data
-
Plaques at
No data.
-
Tangles at
No data.
-
Neuronal Loss at
No data.
-
Gliosis at
No data.
-
Synaptic Loss at
No data.
-
Changes in LTP/LTD at
No data.
-
Cognitive Impairment at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
App | App: Knock-In | Alzheimer's Disease | Unknown. |
Unknown. |
App knock-in (humanized Aβ) (Leuven)
Observed
Absent
-
Plaques at
No plaques observed up to 2 years of age.
-
Tangles at
No tangles observed up to 2 years of age.
No Data
-
Neuronal Loss at
No data.
-
Gliosis at
No data.
-
Synaptic Loss at
No data.
-
Changes in LTP/LTD at
No data.
-
Cognitive Impairment at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
App | App: Knock-In | Alzheimer's Disease | No plaques or tangles were observed up to two years of age. |
Unknown. |
App knock-in (humanized Aβ) (Leuven); Psen1 knock-in (M139T)
Observed
Absent
-
Plaques at
No plaques observed up to 2 years of age.
-
Tangles at
No tangles observed up to 2 years of age.
No Data
-
Neuronal Loss at
No data.
-
Gliosis at
No data.
-
Synaptic Loss at
No data.
-
Changes in LTP/LTD at
No data.
-
Cognitive Impairment at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
App, Psen1 | PSEN1 M139T | App: Knock-In; Psen1: Knock-In | Alzheimer's Disease | No plaques or tangles were observed up to 2 years of age. |
Unknown. |
App knock‐in (Icelandic mutation and humanized Aβ)
Observed
Absent
No Data
-
Plaques at
No data.
-
Tangles at
No data.
-
Neuronal Loss at
No data.
-
Gliosis at
No data.
-
Synaptic Loss at
No data.
-
Changes in LTP/LTD at
No data.
-
Cognitive Impairment at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
App | APP A673T (Icelandic) | App: Knock-In | Alzheimer's Disease | Unknown. |
Unknown. |
App knock‐in (Swedish mutation and humanized Aβ)
Observed
Absent
-
Plaques at
None observed at 3 months.
-
Tangles at
None observed at 3 months.
-
Neuronal Loss at
None observed at 3 months.
No Data
-
Gliosis at
No data.
-
Synaptic Loss at
No data.
-
Changes in LTP/LTD at
No data.
-
Cognitive Impairment at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
App | APP KM670/671NL (Swedish) | App: Knock-In | Alzheimer's Disease | No plaques, neurofibrillary tangles, or neuron loss observed at 3 months, the oldest age reported. |
Unknown. |
App KO/APOE4/Trem2*R47H
Observed
Absent
No Data
-
Plaques at
No data.
-
Tangles at
No data.
-
Neuronal Loss at
No data.
-
Gliosis at
No data.
-
Synaptic Loss at
No data.
-
Changes in LTP/LTD at
No data.
-
Cognitive Impairment at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
APOE, App, Trem2 | TREM2 R47H | APOE: Knock-In; App: Knock-Out; Trem2: Knock-In | Alzheimer's Disease | Unknown. |
Unknown. |
APP NL-F Knock-in
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
-
Tangles at
Absent; although elevated levels of phosphorylated tau are observed in dystrophic neurites around plaques.
-
Neuronal Loss at
Absent.
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 Knock-in
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
-
Tangles at
Absent; although phosphorylated tau is elevated in dystrophic neurites around plaques.
-
Neuronal Loss at
Absent.
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. |
AppNL-G-F/MAPT double knock-in
Observed
-
Plaques at 8
Plaques observed at 2 months.
-
Gliosis at 16
Astrogliosis and microgliosis observed by 4 months.
-
Cognitive Impairment at 52
Deficits in the Y-maze test of working memory at 12 months of age.
Absent
-
Tangles at
No neurofibrillary tangles observed up to 24 months of age.
-
Neuronal Loss at
No neurodegeneration observed up to 24 months of age.
No Data
-
Synaptic Loss at
No data.
-
Changes in LTP/LTD at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
App, MAPT | APP KM670/671NL (Swedish), APP I716F (Iberian), APP E693G (Arctic) | App: Knock-In; MAPT: Knock-In | Alzheimer's Disease | Amyloid plaques, plaque-associated neuritic dystrophy, and neuroinflammation, similar to AppNL-G-F. |
Deficits in the Y-maze test of working memory, similar to AppNL-G-F. |
APPPS1
Observed
-
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).
-
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).
-
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
Observed
-
Plaques at 76
Abundant plaques in hippocampus and subiculum, scattered plaques in cortex.
-
Neuronal Loss at 76
Necrotic neurons in hippocampus and cortex.
-
Cognitive Impairment at 40
Deficits in Barnes maze at 10 months.
Absent
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, PSEN1 | APP KM670/671NL (Swedish), APP V717F (Indiana), PSEN1 L166P | APP: Transgenic; PSEN1: Transgenic | Alzheimer's Disease | Amyloid plaques, cerebral amyloid angiopathy, and necrotic neurons in hippocampus and cortex by 19 months of age. |
Deficits in Barnes maze by 10 months of age. |
APP/PS1/rTg21221
Observed
-
Plaques at 35
Cortical plaques observed between 8-10 months. Plaques larger than in control mice not expressing human tau.
-
Neuronal Loss at 36
Neuronal loss observed adjacent to plaques relative to more distal areas.
-
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: Transgenic | 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. |
AppSAA Knock-in
Observed
-
Plaques at 16
Amyloid plaques seen in AppSAA homozygous mice from 4 months of age and heterozygous mice at 16 months of age.
-
Gliosis at 16
Plaque-associated microgliosis observed by 4 months of age.
Absent
-
Tangles at
AT8-positive dystrophic neurites, but no neurofibrillary tangles, detected in AppSAA homozygous mice at 8 months of age.
No Data
-
Neuronal Loss at
No data.
-
Synaptic Loss at
No data.
-
Changes in LTP/LTD at
No data.
-
Cognitive Impairment at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
App | APP KM670/671NL (Swedish), APP E693G (Arctic), APP T714I (Austrian) | App: Knock-In | Alzheimer's Disease | Homozygotes: Amyloid plaques and plaque-associated microgliosis from 4 months of age; cerebral amyloid angiopathy and dystrophic neurites from 8 months of age. Heterozygotes: Amyloid plaques at 16 months of age. |
Unknown. |
APPsw/0; Pdgfrβ+/-
Observed
-
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.
-
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.
-
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 x NOS2 Knock-out
Observed
-
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).
-
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).
-
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
-
Tangles at
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 | 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
-
Tangles at
Not observed.
-
Neuronal Loss at
There was no difference in neuronal numbers in the cingulate cortex compared with wild-type mice (Xiang et al., 2002).
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 (C3-3 x S-9)
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. |
APPswe/PSEN1dE9 (C57BL6)
Observed
-
Plaques at 16
Amyloid plaques begin to emerge in the cortex at about 4 months of age and in the hippocampus at about 6 months.
-
Gliosis at 17
Plaque-associated astrogliosis and microgliosis are evident by 4 and 8 months, respectively.
-
Synaptic Loss at 18
Synapse loss in the hippocampus occurs by 4 months.
-
Cognitive Impairment at 40
Deficits in the Morris water maze emerge between 6 and 10 months and worsen with age.
Absent
-
Tangles at
Not observed.
-
Neuronal Loss at
Neuron loss has not been observed in mice up to 12 months of age.
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 | Amyloid plaques begin to emerge in the cortex at about 4 months of age and in the hippocampus at about 6 months. Gliosis and dystrophic neurites are associated with plaques. Amyloid angiopathy has been observed in the retina. |
Hyperactivity is apparent by 6 months. Deficits in the Morris water maze emerge between 6 and 10 months and worsen with age. |
APPswe/PSEN1dE9 (line 85)
Observed
-
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).
-
Neuronal Loss at 35
Neuronal loss observed adjacent to plaques relative to more distal areas.
-
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). |
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
-
Plaques at
Absent.
-
Tangles at
Absent.
-
Neuronal Loss 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
-
Tangles at
Dystrophic neurites containing hyperphosphorylated tau, but no tangle pathology.
-
Neuronal Loss at
Absent.
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
-
Tangles at
No tangles or neuropil threads, but some hyperphosphorylated tau by eight months in dystrophic neurites.
-
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.
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. |
Atg16LΔWD
Observed
-
Neuronal Loss at 104
Apparent neuron loss in hippocampi of 2-year-old mice (fewer neurons, increased levels of cleaved caspase-3, and increased numbers of TUNEL-positive neurons).
-
Gliosis at 104
Microgliosis in the hippocampi of 2-year-old mice.
-
Changes in LTP/LTD at 104
Impaired long-term potentiation at CA3-CA1 synapses.
-
Cognitive Impairment at 104
Deficits in the sucrose preference test, spontaneous alternation in the Y-maze, and novel object recognition test.
Absent
-
Plaques at
Intracellular and extracellular Aβ deposits, but no dense-core plaques, in 2-year-old mice.
No Data
-
Tangles at
No data.
-
Synaptic Loss at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
Atg16l1 | Atg16l1: Knock-Out | Alzheimer's Disease | Intracellular and extracellular Aβ deposits, but no dense-core plaques. Microgliosis and neuron loss in 2-year-old mice. |
Deficits in the sucrose-preference test, spontaneous alternation in the Y-maze, and novel object recognition test. |
BACE1 cKO (Hu, Yan) X 5xFAD
Observed
-
Plaques at 11
Accumulate up to day 120, but to a lesser degree than in control 5xFAD, then recede thereafter.
-
Gliosis at 11
Reactive astrocytes and microglia accumulate up to day 120, but to a lesser degree than in control 5xFAD, then recede thereafter.
-
Changes in LTP/LTD at 40
Deficit in LTP at Schaffer collateral–CA1 synapses, but less severe than in control 5xFAD mice.
Absent
-
Cognitive Impairment at
Cued and contextual fear conditioning normal, tested at eight to 10 months of age.
No Data
-
Tangles at
No data.
-
Neuronal Loss at
No data.
-
Synaptic Loss at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
Bace1, APP, PSEN1 | APP KM670/671NL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V | Bace1: Conditional Knock-out; APP: Transgenic; PSEN1: Transgenic | Alzheimer's Disease | Amyloid plaques, reactive astrocytes and microglia, and dystrophic neurites accumulate up to day 120, but to a lesser degree than in control 5xFAD (5xFAD mice homozygous for a floxed Bace1 gene), then recede thereafter. |
Normal contextual and cued fear conditioning, tested at 8 to 10 months of age. |
Bace1 conditional knock-out (adult, whole body) (Vassar)
Observed
Absent
-
Changes in LTP/LTD at
LTP at Schaffer collateral–CA1 synapses was similar in slices obtained from 12-month BACE1-deficient and control mice.
-
Cognitive Impairment at
Normal learning and memory in the Morris water maze, normal alternation in the Y-maze test of working memory, and normal cued and contextual fear conditioning when tested at 9 months of age.
No Data
-
Plaques at
No data.
-
Tangles at
No data.
-
Neuronal Loss at
No data.
-
Gliosis at
No data.
-
Synaptic Loss at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
Bace1 | Bace1: Conditional Knock-out | Alzheimer's Disease | Defects in axonal organization. |
Normal learning and memory in the Morris water maze, normal alternation in the Y-maze test of working memory, and normal cued and contextual fear conditioning; possible hyperactivity in novel situations. |
BACE1 conditional knock-out (Hu, Yan)
Observed
-
Changes in LTP/LTD at 40
Long-term potentiation at Schaffer collateral–CA1 synapses impaired in slices obtained from 10- to 12-month-old mice.
Absent
-
Plaques at
Not observed.
-
Tangles at
Not observed.
-
Neuronal Loss at
Not observed.
-
Gliosis at
No astrogliosis at 1-2 months.
-
Cognitive Impairment at
Contextual and cued fear conditioning normal at 8-10 months.
No Data
-
Synaptic Loss at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
Bace1 | Bace1: Conditional Knock-out | Alzheimer's Disease | No gross morphological changes observed. |
BACE1-deficient mice and Bace1fl/fl mice performed similarly in tests of contextual and cued fear conditioning at 8 to 10 months of age. |
Bace1 conditional knock-out (neonatal, forebrain) (Vassar)
Observed
-
Cognitive Impairment at 24
Delayed learning, but normal memory, in the Morris water maze; normal alternation in the Y-maze test of working memory, normal cued and contextual fear conditioning.
Absent
No Data
-
Plaques at
No data.
-
Tangles at
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 |
---|---|---|---|---|---|
Bace1 | Bace1: Conditional Knock-out | Alzheimer's Disease | Hypomyelination and defects in axon organization. |
Delayed learning, but normal memory, in the Morris water maze; normal alternation in the Y-maze test of working memory, normal cued and contextual fear conditioning. Hyperactivity in when placed in novel environments. |
Bace1 conditional knockout (Tesco)
Observed
-
Changes in LTP/LTD at 60
Deficit in long-term potentiation at Schaffer collateral–CA1 synapses in slices from 14-month-old animals that had received tamoxifen between 8 and 12 weeks of age.
Absent
-
Cognitive Impairment at
Animals that had received tamoxifen between 8 and 12 weeks of age were tested at 4–5 or 12–14 months. Tamoxifen-treated mice performed similarly to vehicle-treated controls in the Y-maze, contextual fear conditioning, pre-pulse inhibition, open field, and light-dark transition tests.
No Data
-
Plaques at
No data.
-
Tangles at
No data.
-
Neuronal Loss at
No data.
-
Gliosis at
No data.
-
Synaptic Loss at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
Bace1 | Bace1: Conditional Knock-out | Alzheimer's Disease | None observed: hippocampal mossy fiber organization and sciatic-nerve myelination were normal. |
Performed similarly to controls in a battery of tests (Y-maze, contextual fear conditioning, pre-pulse inhibition, open field, and light-dark transition task). |
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
-
Tangles at
Absent.
-
Neuronal Loss 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. |
C9-BAC500 (Brown)
Observed
-
Cytoplasmic Inclusions at 40
No cytoplasmic mislocalization, or aggregation of TDP-43 in the motor cortex. However, dipeptide repeats accumulated at advanced age and formed small perinuclear inclusion bodies positive for poly-GP.
Absent
-
Motor Impairment at
No overt motor deficit as measured by the Rotarod and grip strength.
-
Cortical Neuron Loss at
Not observed.
-
Lower Motor Neuron Loss at
Not observed.
-
NMJ Abnormalities at
No difference in denervation of neuromuscular junctions at 24 months of age. No difference in motor or sensory spinal nerve root axon number or morphology.
-
Body Weight at
Non-significant trend for male C9BAC mice to be heavier than non-Tg controls. Female data have not yet been reported.
-
Premature Death at
Normal lifespan beyond 2 years in male mice. Female data have not yet been reported.
-
Gliosis at
No signs of increased activation of microglia or astrocytes in the brain or spinal cord.
No Data
-
Muscle Atrophy at
Muscle histology has not been reported, but no overt muscle atrophy was observed.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
C9orf72 | Hexanucleotide repeat in C9ORF72 | C9orf72: Transgenic | Amyotrophic Lateral Sclerosis, Frontotemporal Dementia | Widespread RNA foci throughout the nervous system starting at 3 months of age, especially comprised of sense transcript. Dipeptide repeats (e.g., poly-GP) as soluble protein and insoluble aggregates. No neurodegeneration. No TDP-43 aggregation, gliosis, inflammation, or synapse loss. |
No overt behavioral abnormalities compared to non-Tg controls. Assessment included grip strength, Rotarod performance, and intruder test. |
C9-BACexp (Baloh/Lutz)
Observed
-
Cytoplasmic Inclusions at 13
RNA foci throughout the nervous system starting at 3 months of age. Foci comprised of RNA transcripts in both the sense and antisense directions. Age-associated formation of dipeptide aggregates, e.g., poly-GP.
Absent
-
Motor Impairment at
No abnormalities in grip strength, Rotarod performance, or open-field testing at a young age (3 months) or advanced age (18 months), compared with non-Tg controls.
-
Cortical Neuron Loss at
Not observed.
-
Lower Motor Neuron Loss at
Not observed.
-
NMJ Abnormalities at
Not observed.
-
Muscle Atrophy at
Not observed.
-
Body Weight at
No abnormalities in body weight at a young age (3 months) or advanced age (18 months) compared with non-Tg controls.
-
Premature Death at
Normal lifespan.
-
Gliosis at
No increase in GFAP staining in the brain and spinal cord compared with non-Tg controls, even at 18 months of age.
No Data
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
C9orf72 | Hexanucleotide repeat in C9ORF72 | C9orf72: Transgenic | Amyotrophic Lateral Sclerosis, Frontotemporal Dementia | Widespread RNA foci throughout the nervous system first assessed at 3 months of age. Soluble dipeptide repeats (e.g., poly-GP) and insoluble aggregates. No neurodegeneration. No TDP-43 aggregation, gliosis, inflammation, or obvious synapse loss. |
No behavioral abnormalities compared to non-Tg controls at either young age (3 months) or advanced age (18 months). Tests included: grip strength, Rotarod performance, open-field, three-chamber, and Y-maze. |
C9ORF72(AAV)(G4C2)149
Observed
-
Motor Impairment at 24
Deficits in the hanging wire test emerge between 3 and 6 months.
-
Cortical Neuron Loss at 24
Cortical neuron loss by 6 months.
-
Cytoplasmic Inclusions at 12
Cytoplasmic inclusions containing dipeptide repeat proteins (DPRs) derived from sense RNA seen in the cortex, hippocampus, cerebellum, and spinal cord; inclusions containing DPRs produced from antisense transcripts seen in the cortex and occasionally in the hippocampus.
-
Gliosis at 12
Astrogliosis in the cortex by 3 months.
Absent
No Data
-
Lower Motor Neuron Loss at
No data.
-
NMJ Abnormalities at
No data.
-
Muscle Atrophy at
No data.
-
Body Weight at
No data.
-
Premature Death at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
C9orf72 | Hexanucleotide repeat in C9ORF72 | C9orf72: Virus | Amyotrophic Lateral Sclerosis, Frontotemporal Dementia | Intranuclear foci containing antisense and antisense repeat RNA; cytoplasmic inclusions containing sense and antisense dipeptide repeat proteins; accumulation of phosphorylated TDP-43 and stress granule-associated proteins; neuron loss and gliosis. |
Motor and cognitive deficits emerge between 3 and 6 months of age. Hyperactivity seen by 3 months. |
C9ORF72(AAV)(G4C2)66
Observed
-
Motor Impairment at 26
At 6 months, 66-repeat mice perform as well as 2-repeat mice on the Rotarod on the first day of testing. However, they fail to improve during subsequent trials, suggesting impairments in coordination and/or motor learning.
-
Cortical Neuron Loss at 26
Compared with mice expressing 2-repeats, the 66-repeat mice had 17 percent fewer neurons in the cortex at 6 months of age and 11 percent fewer Purkinje cells in the cerebellum. At this age neurons in the hippocampus and thalamus were not affected.
-
Cytoplasmic Inclusions at 26
By 6 months, inclusions of C9RAN dipeptides were present in neurons of the cortex and hippocampus, and to a lesser extent in the cerebellum and spinal cord. Inclusions contained polyGA, polyGP, and polyGR dipeptides and were largely ubiquitin-positive.
-
Body Weight at 26
At 6 months females had a lower body weight than mice expressing 2-repeats. Body weight did not differ in males.
-
Gliosis at 26
Astrogliosis in the cortex by 6 months.
Absent
-
Lower Motor Neuron Loss at
At 6 months, neuronal loss in the spinal cord was not detected.
No Data
-
NMJ Abnormalities at
No data.
-
Muscle Atrophy at
No data.
-
Premature Death at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
C9orf72 | Hexanucleotide repeat in C9ORF72 | C9orf72: Virus | Amyotrophic Lateral Sclerosis, Frontotemporal Dementia | Nuclear RNA foci in neurons, dipeptide aggregates (GA, GP, and GR), cytoplasmic inclusions of phosphorylated TDP-43, neuronal loss, brain atrophy, and gliosis. |
Subtle behavioral deficits including anxiety-like behavior, hyperactivity, and antisocial behavior. Subtle motor impairment and failure to improve on the Rotarod. |
C9orf72 Knock-out
Observed
-
Motor Impairment at 39
Reduced activity on open-field test. No abnormalities in grip strength or Rotarod performance.
Absent
-
Cortical Neuron Loss at
Not observed.
-
Lower Motor Neuron Loss at
Not observed.
-
Cytoplasmic Inclusions at
Not observed.
-
NMJ Abnormalities at
Not observed.
-
Muscle Atrophy at
Not observed.
-
Body Weight at
Not observed.
-
Premature Death at
Not observed.
-
Gliosis at
Not observed.
No Data
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
C9orf72 | C9orf72: Knock-Out | Frontotemporal Dementia, Amyotrophic Lateral Sclerosis | Chromatolytic structures are observed with H&E staining, in gray and white matter of the spinal cord. Neurodegeneration not present. |
Normal sensorimotor coordination and limb strength. Reduced activity in open-field test. |
CamKII;(GR)80
Observed
-
Cortical Neuron Loss at 24
Neuron loss in the cortex, beginning between 3 and 6 months of age.
-
Gliosis at 24
Microgliosis and astrogliosis evident at 6 and 9 months, respectively.
Absent
-
Motor Impairment at
No difference between CamKII;(GR)80 mice and CamKII-tTA control mice up to 9 months of age.
-
Cytoplasmic Inclusions at
No TDP-43 inclusions seen in mice studied up to 8 months of age.
-
Body Weight at
No difference between CamKII;(GR)80 mice and CamKII-tTA control mice up to 11 months of age.
No Data
-
Lower Motor Neuron Loss at
No data, but note that the transgene is not expressed in these neurons.
-
NMJ Abnormalities at
No data.
-
Muscle Atrophy at
No data.
-
Premature Death at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
Transgenic | Amyotrophic Lateral Sclerosis, Frontotemporal Dementia | Neuron loss in the frontal cortex, beginning between 3 and 6 months of age. Microgliosis and astrogliosis evident at 6 and 9 months, respectively. No TDP-43 inclusions seen in mice studied up to 8 months of age. DNA damage and mitochondrial abnormalities observed. |
Deficits in social behavior and increased anxiety emerge between 3 and 6 months. Working memory is intact at least through 9 months of age. |
CAST.APP/PS1
Observed
-
Plaques at 32
Thioflavin S-positive amyloid plaques are present in the cortex and hippocampus by 8 months of age, with more severe plaque pathology in females than in males.
-
Neuronal Loss at 34
Compared with their non-transgenic littermates, CAST.APP/PS1 mice have fewer neurons in area CA1 of the hippocampus. Cortical neuron numbers do not differ between the genotypes.
-
Gliosis at 33
Plaque-associated microgliosis observed by 8 months.
-
Cognitive Impairment at 31
Deficits in short-term memory by 8 months in males (data from females unavailable).
Absent
-
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: deltaE9 | APP: Transgenic; PSEN1: Transgenic | Alzheimer's Disease | Amyloid plaques, plaque-associated gliosis, cerebral amyloid angiopathy; possible neuron loss in hippocampal area CA1. |
Transgenic mice are hyperactive. Working memory (spontaneous alternation in the Y-maze) is normal at 7 to 8 months, but short-term memory (tested in the Y-maze) is impaired in males (data from females is not available, as wild-type females are unable to perform this test). |
Ceacam1 KO/APOE4/Trem2*R47H
Observed
Absent
No Data
-
Plaques at
No data.
-
Tangles at
No data.
-
Neuronal Loss at
No data.
-
Gliosis at
No data.
-
Synaptic Loss at
No data.
-
Changes in LTP/LTD at
No data.
-
Cognitive Impairment at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
APOE, Ceacam1, Trem2 | TREM2 R47H | APOE: Knock-In; Ceacam1: Knock-Out; Trem2: Knock-In | Alzheimer's Disease | Unknown. |
Unknown. |
Clasp2*L163P/APOE4/Trem2*R47H
Observed
Absent
No Data
-
Plaques at
No data.
-
Tangles at
No data.
-
Neuronal Loss at
No data.
-
Gliosis at
No data.
-
Synaptic Loss at
No data.
-
Changes in LTP/LTD at
No data.
-
Cognitive Impairment at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
Clasp2, APOE, Trem2 | TREM2 R47H | Clasp2: Knock-In; APOE: Knock-In; Trem2: Knock-In | Alzheimer's Disease | Unknown. |
Unknown. |
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
-
Tangles at
No data.
-
Neuronal Loss 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
-
Tangles at
No data.
-
Neuronal Loss 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
-
Tangles at
No data.
-
Neuronal Loss 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. |
Endogenous Sod1 D83G
Observed
-
Motor Impairment at 6
Both male and female mice develop a variety of progressive motor symptoms. Grip strength was reduced at 6 weeks of age. Tremors developed by about 5 months of age. Rotarod performance was impaired, at 23 weeks in females and 67 weeks in males.
-
Cortical Neuron Loss at 29
Neuronal numbers comparable to wild-type at 15 weeks, but about 20 percent loss of upper motor neurons by 29 weeks. Neurons in layer V of the motor cortex appeared selectively vulnerable.
-
Lower Motor Neuron Loss at 15
Neuronal numbers comparable to wild-type at 6 weeks, but loss occurred by 15 weeks. The neuronal loss then stabilized; it was not more severe at 52 weeks of age.
-
NMJ Abnormalities at 52
Denervation of a hindlimb muscle, the extensor digitorum longus, was detected by 52 weeks of age, and a decreased number of motor units in the EDL muscle.
-
Body Weight at 4
Homozygous mice, both male and female, showed reduced body weight by 4 weeks of age in contrast to wild-type littermates. Loss of excessive body weight was the primary factor leading to euthanasia.
-
Premature Death at 71
Males reach end-stage sooner than females (495 ± 22 versus 588 ± 24 days). Animals were sacrificed when weight loss exceeded 20 percent of maximum weight, in accordance with animal-use guidelines. This is likely explained by the development of hepatocellular carcinomas due to SOD1 loss of function.
-
Gliosis at 15
Gliosis, of both astrocytes and microglia, was evident in the spinal cord by 15 weeks. It was further elevated at 52 weeks.
Absent
-
Cytoplasmic Inclusions at
Not observed.
No Data
-
Muscle Atrophy at
Muscle atrophy was not reported, although changes to the muscle composition and histochemistry were observed.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
SOD1 | D83G in SOD1 | SOD1: Other | Amyotrophic Lateral Sclerosis | Upper and lower motor neuron loss in specific regions (layer V of motor cortex and lumbar spinal cord). Gliosis in spinal cord. Denervation of hindlimb muscle. |
Progressive motor impairments, including tremor, gait abnormalities, decreased grip strength, and impaired Rotarod performance. |
FUSΔ14 (FUSd14)
Observed
-
Cytoplasmic Inclusions at 13
Neuronal cytoplasmic inclusions were present by 3 months of age in the cerebral cortex. Inclusions occurred in about 20% of neurons and often co-labeled with ubiquitin.
Absent
-
Motor Impairment at
When the mice were sacrificed at 3 months of age, they appeared healthy and displayed no obvious motor phenotype.
-
Cortical Neuron Loss at
Not observed.
-
Lower Motor Neuron Loss at
Not observed.
-
Gliosis at
No obvious astrogliosis or microglial activation at 3 months of age in the cerebral cortex.
No Data
-
NMJ Abnormalities at
No data.
-
Muscle Atrophy at
No data.
-
Body Weight at
No data.
-
Premature Death at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
FUS | FUS Δ14 | FUS: Virus | Frontotemporal Dementia, Amyotrophic Lateral Sclerosis | Widespread neuronal cytoplasmic inclusions (NCIs) by 3 months of age. Inclusions were FUS-positive and often co-labeled with ubiquitin. No overt neurodegeneration or reactive gliosis. |
No overt motor phenotypes at 3 months of age. |
FUSDelta14 Knock-in
Observed
-
Motor Impairment at 65
Normal motor activity at 3 months of age but impaired hindlimb function by 15 months.
-
Lower Motor Neuron Loss at 50
No lower motor neuron loss at 3 months but 14% reduction in the number of motor neurons in lumbar spinal cord at 12 months and 20% reduction by 18 months.
-
NMJ Abnormalities at 78
Reduction in the number of intact neuromuscular junctions (fully innervated endplates) in hindlimb lumbrical muscles by 18 months of age.
-
Premature Death at 82
Reduced survival starting at 19 months of age.
Absent
-
Cytoplasmic Inclusions at
No increase in the number of spinal motor neurons that contain p62- or ubiquitin-positive inclusions in aged FUSDelta14 mice compared with aged wild-type mice.
No Data
-
Cortical Neuron Loss at
No data.
-
Muscle Atrophy at
No data.
-
Body Weight at
No data.
-
Gliosis at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
FUS | FUSDelta14 truncation mutation | FUS: Knock-In | Amyotrophic Lateral Sclerosis | Progressive (not developmental) loss of lumbar spinal motor neurons, starting by 12 months of age; partial denervation of hindlimb muscles. Mislocalization of mutant FUS from nucleus to cytoplasm. |
Hindlimb motor impairment by 15 months. |
FusΔNLS
Observed
-
Motor Impairment at 0
By 10 months, mice demonstrated irregular walking patterns and reduced hang time on the inverted grid test. No deficits in grip strength or rotarod performance. Paralysis was not observed.
-
Lower Motor Neuron Loss at 0
Approximately 30% reduction of motor neuron numbers in the dorsal spinal cord.
-
Cytoplasmic Inclusions at 0
Ubiquitin pathology was observed in motor neurons, but p62 inclusions were not.
-
NMJ Abnormalities at 0
Fibrillation and fasciculation potentials were observed in the gastrocnemius or tibialis anterior muscles. There was also a reduction in compound muscle action potential amplitude.
-
Gliosis at 0
Slight increase in oligodendrocytes in the spinal cord white matter.
Absent
-
Body Weight at
By 22 months, no weight loss was observed.
-
Premature Death at
Life span was not altered.
No Data
-
Cortical Neuron Loss at
No data.
-
Muscle Atrophy at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
Fus | FUS ΔNLS | Fus: Knock-In | Amyotrophic Lateral Sclerosis | The spinal cord exhibited FusΔNLS mislocalization, a loss of motor neurons, and ubiquitin pathology. |
No impairments in grip strength or rotarod performance. Irregular walking patterns and reduced hang time on inverted grid test were observed. |
FUS-R521C
Observed
-
Motor Impairment at 0
Early postnatal motor impairment, including abnormal hindlimb clasping when lifted by the tail, gait abnormalities, and impaired Rotarod performance.
-
Lower Motor Neuron Loss at 2
No detectable difference in spinal motor neurons at P0. At P16, about 20% loss of ChAT-positive neurons in the anterior horn of cervical spinal cord. At P30-P60, about 50% loss of anterior horn neurons. Remaining motor neurons show reduced dendritic complexity and synaptic density.
-
Cytoplasmic Inclusions at 0
Less than 10% of spinal motor neurons have cytoplasmic FUS inclusions.
-
NMJ Abnormalities at 0
Reduced innervation of neuromuscular junctions in the diaphragm.
-
Muscle Atrophy at 0
The majority of mice have severe skeletal muscle atrophy in the hindlimb by end stage.
-
Body Weight at 0
Early postnatal growth is retarded, and the mice experience progressive loss of body weight.
-
Premature Death at 0
The majority of mice in the N1F1 generation reached end stage and were sacrificed by postnatal day 100. Mice in subsequent generations live longer: about 40% reach end stage by postnatal day 200.
-
Gliosis at 0
Prominent increase in microgliosis and astrogliosis in the anterior horn of the spinal cord by end stage.
Absent
-
Cortical Neuron Loss at
No detectable loss of cortical neurons; however, neurons in the sensorimotor cortex show reduced dendritic complexity and reduced synaptic density.
No Data
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
FUS | FUS R521C | FUS: Transgenic | Amyotrophic Lateral Sclerosis, Frontotemporal Dementia | Robust neurodegeneration in the anterior horn of the spinal cord, including about 50% loss of neurons by end stage. Prominent microgliosis and astrogliosis in the anterior horn at end stage. Very rare cytoplasmic FUS inclusions. |
A variety of motor impairments from a young age, including spastic paraplegia, abnormal hindlimb clasping, gait abnormalities, and impaired performance on the Rotarod. |
hAbeta-loxP-KI
Observed
Absent
No Data
-
Plaques at
No data.
-
Tangles at
No data.
-
Neuronal Loss at
No data.
-
Gliosis at
No data.
-
Synaptic Loss at
No data.
-
Changes in LTP/LTD at
No data.
-
Cognitive Impairment at
No data.
Genes | Mutations | Modification | Disease | Neuropathology | Behavior/Cognition |
---|---|---|---|---|---|
APP | APP: Knock-In | Alzheimer's Disease | Unknown. |
Unknown. |
hAPP/APOE4/Trem2*R47H
Observed
Absent
No Data
-
Plaques at
No data.
-
Tangles at
No data.
-
Neuronal Loss at
No data.
-
Gliosis at
No data.
-
Synaptic Loss at
No data.
-
Changes in LTP/LTD at