Genes: APP, PSEN1, MAPT
Mutations: APP KM670/671NL (Swedish), MAPT P301L, PSEN1 M146V
Modification: APP: Transgenic; PSEN1: Transgenic; MAPT: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: B6;129-Psen1
Genetic Background: (129X1/SvJ x 129S1/Sv)F1-Kitl<+>
Availability: The Jackson Lab; available through the JAX MMRRC Stock# 034830; Live
These widely-used mice contain three mutations associated with familial Alzheimer's disease (APP Swedish, MAPT P301L, and PSEN1 M146V). The mice are viable, fertile, and display no initial gross physical or behavioral abnormalities. Translation of the overexpressed transgenes appears restricted to the central nervous system, including the hippocampus and cerebral cortex. These mice display both plaque and tangle pathology. Aβ deposition is progressive, with intracellular immunoreactivity detected in some brain regions as early as 3 to 4 months of age. Extracellular Aβ deposits appear by six months in the frontal cortex and become more extensive by twelve months. Changes in tau occur later; by 12 to 15 months aggregates of conformationally-altered and hyperphosphorylated tau are detected in the hippocampus (Oddo et al., 2003; Billings et al., 2005).
Age-related, progressive neuropathology including plaques and tangles. Extracellular Aβ deposits by six months in frontal cortex, which become more extensive by twelve months. Although tau pathology is not observed at six months, it is evident by twelve months. Synaptic dysfunction, including LTP deficits, occur prior to plaques and tangles.
Cognitive impairment is observed by four months. Impairments first manifest as a retention/retrieval deficit and not as a learning deficit, and occur prior to plaques and tangles. Deficits are observed in both spatial and contextual based paradigms. Clearance of intraneuronal Aβ by immunotherapy rescues the early cognitive deficits in a hippocampal-dependent task.
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). The transgenes integrated at a single locus under the control of the mouse Thy1.2 promoter.
This model was formerly available through The Jackson Lab as Stock# 004807.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Neuronal Loss
Extracellular Aβ deposits by 6 months in the frontal cortex, predominantly layers 4 and 5 and progress with age (Oddo et al., 2003).
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).
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
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 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).
- Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM. Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron. 2003 Jul 31;39(3):409-21. PubMed.
- Billings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM. Intraneuronal Abeta causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice. Neuron. 2005 Mar 3;45(5):675-88. PubMed.
- Blázquez G, Cañete T, Tobeña A, Giménez-Llort L, Fernández-Teruel A. Cognitive and emotional profiles of aged Alzheimer's disease (3×TgAD) mice: effects of environmental enrichment and sexual dimorphism. Behav Brain Res. 2014 Jul 15;268:185-201. Epub 2014 Apr 15 PubMed.
- Martin SA, Jameson CH, Allan SM, Lawrence CB. Maternal high-fat diet worsens memory deficits in the triple-transgenic (3xTgAD) mouse model of Alzheimer's disease. PLoS One. 2014;9(6):e99226. Epub 2014 Jun 11 PubMed.