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)
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
PSEN1(M146V) (line 8.9) Swiss Webster x B6D2F1 PSEN1 PSEN1 M146V Transgene containing human PSEN1 with the M146V mutation driven by the rat PDGF-β promoter. PSEN1: Transgenic Alzheimer's Disease No abnormal neuropathology up to 2.5 years. Elevated Aβ42(43). Altered mitochondrial activity and disregulation of calcium homeostasis. Unknown. Medium and late after hyperpolarizations in CA3 pyramidal cells were larger compared with nontransgenic or mice transgenic for wild-type PSEN1. Available through the Technology Transfer Office, Patents & Licensing, University of South Florida. Duff et al., 1996 No
PS1M146V KI B6.129-Psen1tm1Mpm/J C57BL/6 PSEN1 PSEN1 M146V Point mutations were introduced into exon 5 of the endogenous mouse PSEN1 gene altering the codons corresponding to amino acids 145 and 146 from isoleucine and methionine to valine and valine, respectively. The targeting vector contained a lox-P flanked neomycin resistance cassette and herpes simplex virus thymidine kinase genes. PSEN1: Knock-In Alzheimer's Disease Hypersensitive to kainate-induced degeneration and death of CA3, CA1 and hilar neurons. Cultured hippocampal neurons have increased vulnerability to death induced by glutamate. Disrupted calcium homeostasis. Increased oxidative stress and mitochondrial dysfunction. Unknown. Mice are viable, fertile, and normal in size. No gross physical or behavioral abnormalities. The Jackson Lab: Stock# 004193; Cryopreserved Guo et al., 1999 No

1 Visualizations

Phenotypes Examined

  • Plaques
  • Tangles
  • Neuronal Loss
  • Gliosis
  • 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+.

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.