Research Models

Selected Results

3 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 (3)
5XFAD APP/PS1, Tg6799, Tg-5xFAD B6SJL-Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax (C57BL/6 x SJL)F1 APP, PSEN1 APP KM670/671NL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V Two transgenes: mutant human APP with the APP Swedish, Florida and London mutations and containing the 5' untranslated region driven by the mouse Thy1 promoter and 2) mutant human PSEN1 including the M146L and L286V mutations driven by the mouse Thy1 promoter. APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Amyloid pathology starting at 2 months, including amyloid plaques. Accumulation of intraneuronal Aβ before amyloid deposition. Gliosis and synapse degeneration. Neuron loss in cortical layer 5 and subiculum. No neurofibrillary tangles. Age-dependent memory deficits including spatial memory, stress-related memory, and memory stablization. Motor phenotype and reduced anxiety. The Jackson Lab; available through the JAX MMRRC Stock# 034840; Live Oakley et al., 2006 Yes
PSEN1(M146L), PS1 (M146L) line 5.1 Swiss Webster x B6D2F1 PSEN1 PSEN1 M146L (A>C) Transgene containing human PSEN1 with the M146L mutation driven by the rat PDGF-β promoter. PSEN1: Transgenic Alzheimer's Disease No abnormal pathology up to 2.5 years. Elevated Aβ2(43); no effect on Aβ40. Altered mitochondrial activity. Disregulation of calcium homeostasis. No difference from wild-type mice in the “Y” maze (alternation performance or activity) at 12-14 weeks. Elevated PSEN1 expression (2-3 fold). Medium and late after hyperpolarizations in CA3 pyramidal cells were larger compared with wild-type mice. Larger calcium responses to depolarization. Stronger synaptic potentiation of the CA3 to CA1 projection. Available through the Technology Transfer Office, Patents & Licensing, University of South Florida. Duff et al., 1996 No
PS1 + APP, PSAPP Swiss Webster, B6D2F1, C57Bl/6SJL, C57Bl/6 APP, PSEN1 APP KM670/671NL (Swedish), PSEN1 M146L (A>C) These double transgenic mice were generated by crossing mice overexpressing human APP with the Swedish mutation driven by the hamster prion protein gene promoter (the Tg2576 model) with mice overexpressing human PSEN1 with the M146L mutation driven by the PDGF-β promoter (PSEN1(M146L), line 5.1). The two transgenes segregate independently. APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease Aβ accumulates in the cerebral cortex and hippocampus starting ~6 months and increasing with age. Other regions affected later. Deposition occurs in white matter,  cerebrovasculature, and grey matter in the form of diffuse and fibrillar plaques. Fibrillar deposits are associated with dystrophic neurites and GFAP-positive astrocytes at ~ 6 months with later microglial activation. Progressive impairment between 5–7 and 15–17 months in some tests of cognitive performance, but not others. No change in anxiety levels. Selective increase in brain Aβ42(43) in the double transgenics (41% increase at 6 weeks) compared to Tg2576 single transgenic, which had unchanged Aβ40 and Aβ42(43) at this age. Tg2576 mice are available through Taconic (Stock #001349) and Charles River. The PS1(M146L) line is available through the Technology Transfer Office, Patents & Licensing, University of South Florida. Holcomb et al., 1998 Yes

2 Visualizations

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: 1mo, 3mo, 6mo, 9mo, 1yr, 15mo, 18mo+.

5xFAD

Observed
  1. Plaques at 7

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

  2. Neuronal Loss at 39

    Neuron loss in cortical layer 5 and subiculum.

  3. Gliosis at 9

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

  4. Synaptic Loss at 39

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

  5. Changes in LTP/LTD at 26

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

  6. Cognitive Impairment at 17

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

Absent
  • Tangles at

    Absent.

Unknown
Genes Mutations Modification Disease Neuropathological
Phenotype
Neurological/Behavioral
Phenotype
APP, PSEN1 APP KM670/671NL (Swedish), APP I716V (Florida), APP V717I (London), PSEN1 M146L (A>C), PSEN1 L286V APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

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

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

PS/APP

Observed
  1. Plaques at 26

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

  2. Neuronal Loss at 79

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

  3. Gliosis at 26

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

  4. Cognitive Impairment at 12

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

Absent
  • Tangles at

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

Unknown
  • Synaptic Loss at

    Unknown.

  • Changes in LTP/LTD at

    Unknown.

Genes Mutations Modification Disease Neuropathological
Phenotype
Neurological/Behavioral
Phenotype
APP, PSEN1 APP KM670/671NL (Swedish), PSEN1 M146L (A>C) APP: Transgenic; PSEN1: Transgenic Alzheimer's Disease

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

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