Research Models

Selected Results

6 Models

Name Other Names Strain Name Genetic Background Gene Mutation Modification Info Modification Disease Neuropathological
Phenotype
Cognition/ Behavior Other Phenotype Availability Primary Paper Visualization
Mouse Models (6)
3xTg-AD, The LaFerla mouse B6;129-Psen1<tm1Mpm> Tg(APPSwe,tauP301L)1Lfa/Mmjax (129X1/SvJ x 129S1/Sv)F1-Kitl<+> APP, PSEN1, MAPT APP KM670/671NL (Swedish), MAPT P301L, PSEN1 M146V Single-cell embryos from mice with knock-in of PSEN1 with the PS1M146V mutation were injected with two human transgenes (APP with the Swedish mutation and MAPT with the P30IL mutation). Transgenes integrated at a single locus under the control of the mouse Thy1.2 promoter. APP: Transgenic; PSEN1: Transgenic; MAPT: Transgenic Alzheimer's Disease Age-related, progressive neuropathology including plaques and tangles. Extracellular Aβ deposits by 6 months in frontal cortex, more extensive by 12 months. No tau pathology at 6 months, but evident at 12 months. Synaptic dysfunction, including LTP deficits, prior to plaques and tangles. Cognitive impairment by 4 months. Impairments first manifest as a retention/retrieval deficit and not as a learning deficit, and occur prior to plaques and tangles. Deficits in both spatial and contextual based paradigms. Clearance of intraneuronal Aβ by immunotherapy rescues the early cognitive deficits in a hippocampal-dependent task. The Jackson Lab; available through the JAX MMRRC Stock# 034830; Live Oddo et al., 2003 Yes
TauP301L-JNPL3 Tg(Prnp-MAPT*P301L)JNPL3Hlmc C57BL/6, DBA/2, SW Mixed Background MAPT MAPT P301L Transgene for human MAPT (4R0N) with the P301L mutation driven by the mouse prion promoter. MAPT: Transgenic Frontotemporal Dementia, Progressive Supranuclear Palsy, Alzheimer's Disease Age and gene-dose dependent development of neurofibrillary tangles as early as 4.5 months in homozygotes and 6.5 months in heterozyotes. Tangles and Pick-body-like inclusions in the amygdala, hypothalamus, pons, medulla, and spinal cord among other areas. Neuronal loss, especially in the spinal cord. By 10 months, 90% developed motor and behavioral disturbances including limb weakness, hunched posture, decrease in grooming and vocalization. Eye irritiation, possibily due to carrying the Pde6brd1 retinal degeneration mutation carries Pde6brd1 mutation Taconic: Stock#2508 (homozygote), #1638 (heterozygote and wild-type) Lewis et al., 2000 Yes
rTg4510, Tg(tetO-TauP301L)4510, Tau P301L FVB-Tg(tetO-MAPT*P301L)#Kha/JlwsJ, STOCK Tg(Camk2a-tTA)1Mmay Tg(tetO-MAPT*P301L)#Kha/J FVB/N MAPT MAPT P301L Transgene has human four-repeat MAPT lacking the amino terminal sequence (4R/0N) with the P301L mutation. Expression is driven by a tetracycline operator (tetO) upstream of a cytomegalovirus minimal promoter and contains exons 2-3 of the mouse prion protein gene (Prnp) untranslated sequence. MAPT: Transgenic Alzheimer's Disease, Frontotemporal Dementia Argyrophilic tangle-like inclusions in cortex by 4 months and in hippocampus by 5.5 months. Decreased CA1 neurons (~60%) by 5.5 months. Gross forebrain atrophy by 10 months. The number of CA1 neurons stabilized after a brief (6 to 8 weeks) 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. When the transgene was suppressed with dox at 2.5 months spatial memory improved. Homozygous mice are not viable. The Jackson Lab: Stock# 015815 (single transgenic line); Live;  The Jackson Lab: Stock# 024854 (double transgenic line); Under Development Santacruz et al., 2005 Yes
Tau.P301L, hTau.P301L, Tau-4R-P301L, Tau(P301L) Thy1-hTau.P301L FVB/N MAPT MAPT P301L These transgenic mice overexpress the human Tau-4R/2N isoform bearing the P301L mutation under the control of the neuron-specific murine Thy1 promoter. MAPT: Transgenic Frontotemporal Dementia, Alzheimer's Disease Pathologic hyperphosphorylation and conformational change of parenchymal tau in brain tissues starting at 7 months. Tangle-like pathology is mainly observed in the brain stem and spinal cord, and to a lesser extent in the midbrain and cerebral cortex. Age-dependent increase in total tau in CSF. Age-associated deficits in a passive avoidance task (starting at 5 months) and a novel object recognition task (starting at 9 months). At a young age (~2 months) outperforms wild-type littermates in object recognition memory. Progressive motor impairment and reduced activity, accompanied by increased clasping of hind and then forelimbs around seven months. Premature death around 8-12 months, preceded by weight loss, hyperkyphosis, reduced activity, and upper airway dysfunction. Available through reMYND. Terwel et al., 2005 Yes
Triple transgenic, 3Tg B6.D2-Tg(Thy1-APPSwe, Prp-PSEN2N141I, Thy1-TauP301L) C57BL/6, DBA/2; backcrossed to C57BL/6 APP, MAPT, PSEN2 APP KM670/671NL (Swedish), MAPT P301L, PSEN2 N141I (Volga German) PS2APP mice (line B6.152H) x tau mice (line B6.TauP301L). PS2APP were generated by co-injecting two transgenic constructs: human PSEN2 (N141I mutation) and human APP (Swedish mutation) driven by the mouse prion promoter and the mouse Thy1 promoter respectively. The transgenic TauP301L mouse (line pR5) expresses the human tau40 isoform driven by the Thy1.2 promoter. APP: Transgenic; MAPT: Transgenic; PSEN2: Transgenic Alzheimer's Disease Phosphorylated tau accumulation in the subiculum and the CA1 region of the hippocampus at 4 months. Neurofibrillary tangles in these regions as well as the amygdala. Amyloid plaques. Dystrophic neurites and neuropil threads containing abnormally phosphorylated tau. No overt neuronal loss. Impaired spatial learning in the Morris water maze at 4 months but impairment is not progressive between 4 and 12 months and appears to be independent of pathology. Cortex-specific deficiencies in oxidative phosphorylation. Loss of mitochondrial membrane potential. Reduced cortical ATP. Increased superoxide anions and ROS compared to wild-type. No differences in APP expression, APP cleavage or Aβ accumulation compared to PS2APP. Levels of ptau422 increased in an age-dependent manner, but levels of ptau231 did not. Available through Laurence Ozmen. Grueninger et al., 2010 Yes
APPSwe-Tau, APPSwe(2576)/TauJNPL3, TAPP Tg(APPSWE)2576Kha Tg(Prnp-MAPT*P301L)JNPL3Hlmc C57BL/6, DBA/2, SJL, SW Mixed Background APP, MAPT APP KM670/671NL (Swedish), MAPT P301L Generated by crossing Tg2576 mice, which have the transgene for human APP (isoform 695) carrying the Swedish mutation with mice expressing human MAPT (4 repeat) with the P301L mutation. APP; MAPT: Transgenic Alzheimer's Disease Gradual appearance of plaques; by 9 months plaques are scattered throughout the cortex, hippocampus, and amygdala similar to Tg2576. Tau pathology more extensive than JNPL3. Astrocytosis and microgliosis. Motor disturbances similar to JNPL3, with identical range in age of onset. Reduced vocalization and decreased grooming. Progressive hindlimb weakness. Hunched posture. Eye irritations. Some mice have the Pde6brd1 retinal degeneration mutation which can cause light sensitivity and/or blindness and may affect behavioral testing. Taconic: Stock# 2469 Lewis et al., 2001 Yes

6 Visualizations

Phenotypes Examined

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

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

3xTg

Observed
  1. Plaques at 26

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

  2. Tangles at 52

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

  3. Gliosis at 30

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

  4. Changes in LTP/LTD at 26

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

  5. 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
Unknown
  • Neuronal Loss at

    Unknown.

Genes Mutations Modification Disease Neuropathological
Phenotype
Neurological/Behavioral
Phenotype
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.

JNPL3(P301L)

Observed
  1. 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).

  2. Neuronal Loss at 43

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

  3. 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.

Unknown
  • Cognitive Impairment at

    Unknown.

Genes Mutations Modification Disease Neuropathological
Phenotype
Neurological/Behavioral
Phenotype
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.

rTg(tauP301L)4510

Observed
  1. 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 (SantaCruz et al., 2005).

  2. 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 (SantaCruz et al., 2005).

  3. Synaptic Loss at 35

    Significant loss of dendritic spines at 8-9 months (~30% decrease in spine density in somatosensory cortex)(Kopeikina et al., 2013).

  4. Cognitive Impairment at 11

    No significant abnormalities at 1.3 months but the retention of spatial memory examined by 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 (SantaCruz et al., 2005).

Absent
  • Plaques at

    Absent.

Unknown
Genes Mutations Modification Disease Neuropathological
Phenotype
Neurological/Behavioral
Phenotype
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%) by 5.5 months. Gross forebrain atrophy by 10 months. The number of CA1 neurons stabilized after a brief (6 to 8 weeks) 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. When the transgene was suppressed with dox at 2.5 months spatial memory improved.

Tau P301L

Observed
  1. Tangles at 35

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

  2. Gliosis at 30

    Astrogliosis by 7 months.

  3. Changes in LTP/LTD at 26

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

  4. 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.

Unknown
  • 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 Neuropathological
Phenotype
Neurological/Behavioral
Phenotype
MAPT MAPT P301L MAPT: Transgenic Frontotemporal Dementia, Alzheimer's Disease

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.

TauPS2APP

Observed
  1. Plaques at 17

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

  2. Tangles at 70

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

  3. 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).

Unknown
  • Gliosis at

    Unknown.

  • Synaptic Loss at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathological
Phenotype
Neurological/Behavioral
Phenotype
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.

Tg2576/Tau(P301L) (APPSwe-Tau)

Observed
  1. Plaques at 39

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

  2. Tangles at 13

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

  3. 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
Unknown
  • Synaptic Loss at

    Unknown.

Genes Mutations Modification Disease Neuropathological
Phenotype
Neurological/Behavioral
Phenotype
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.