Mutations: APP V717F (Indiana)
Modification: APP: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: C57B6 x DBA2
As originally described, these mice exhibit high human APP expression, greater than 10-fold higher than endogenous murine APP. Because the construct allows for alternative splicing, multiple isoforms are produced including APP 695, 751 and 770. These mice exhibit extracellular Aβ deposition, dystrophic neurites, gliosis, and loss of synaptic and dendritic density in the hippocampus (Games et al., 1995). They show a variety of cognitive deficits from an early age, some of which occur prior to plaque deposition and some of which are age-related (Dodart et al., 1999; Gerlai et al., 2002; Chen et al., 2000).
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
In heterozygous mice no plaque pathology at 4-6 months. At 6-9 months mice begin to exhibit deposits of human Aβ in the hippocampus, corpus callosum, and cerebral cortex. Plaques become more extensive with age and vary in size and structure including diffuse irregular plaques and compact cored plaques (Games et al., 1995).
No paired helical filaments or aggregates, but phosphorylated tau immunoreactivity is observed in dystrophic neurites after 14 months (Masliah et al., 2001).
GFAP-positive astrocytes and activated microglia associated with plaques (Games et al., 1995).
Decreased synaptic density in the dentate gyrus as measured by synaptophysin immunoreactivity. Also decreased dendritic density as measured by MAP2 immunoreactivity (Games et al., 1995).
Changes in LTP/LTD
Alterations in LTP induced by theta burst stimulation at 4-5 months which is prior to plaque formation; although the potentiation immediately after TBS was comparable to control mice, the potentiation decayed more rapidly in PDAPP mice. Also paired pulse facilitation was enhanced. Responses to high frequency stimulation bursts were distorted (Larson et al., 1999).
Deficits in a variety of memory paradigms from a young age. Robust deficits in the radial arm maze at 3 months (deficits appear before amyloid plaque deposits). Object recognition, 6, 9-10 months. Operant learning, 3, 6 months (Dodart et al., 1999).
- Games D, Adams D, Alessandrini R, Barbour R, Berthelette P, Blackwell C, Carr T, Clemens J, Donaldson T, Gillespie F. Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature. 1995 Feb 9;373(6514):523-7. PubMed.
- Dodart JC, Meziane H, Mathis C, Bales KR, Paul SM, Ungerer A. Behavioral disturbances in transgenic mice overexpressing the V717F beta-amyloid precursor protein. Behav Neurosci. 1999 Oct;113(5):982-90. PubMed.
- Gerlai R, Fitch T, Bales KR, Gitter BD. Behavioral impairment of APP(V717F) mice in fear conditioning: is it only cognition?. Behav Brain Res. 2002 Nov 15;136(2):503-9. PubMed.
- Chen G, Chen KS, Knox J, Inglis J, Bernard A, Martin SJ, Justice A, McConlogue L, Games D, Freedman SB, Morris RG. A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer's disease. Nature. 2000 Dec 21-28;408(6815):975-9. PubMed.
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