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- W2110367560 abstract "Mutations in the amyloid precursor protein (APP) and presenilin-1 (PS1) genes are independent causes of early-onset familial Alzheimer's disease (AD). Yet, transgenic mouse models that express mutant human (mh) APP alone or in combination with mhPS1 have failed to recapitulate all of the key AD hallmarks: 1) β-amyloid plaques, 2) tauopathy, 3) neuronal loss, and 4) cognitive impairment. This key deficiency in the mouse models has been used by some as evidence against the “amyloid cascade hypothesis” of AD. Because rats are 4-5 million years closer in evolution to humans than mice are, we hypothesized that rats would be a more suitable species within which to model the disease. We generated a transgenic rat model that co-expresses “Swedish” mhAPP and deltaE9 mhPS1 on a Fischer 344 background (line TgF344-AD). We then assessed brain pathology at light microscopic and ultrastructural levels, performed Aβ and tau biochemical analyses, and assayed behavioral impairment in TgF344-AD rats. With age, these rats manifest all of the AD pathological hallmarks. Specifically, β-amyloid deposits occur in small number as early as 6 months of age, and become extensive by 15-27 months, when pathologic tau and neurofibrillary “tangles” are present. These AD-type pathologies occur along with dramatic loss of cortical and hippocampal neurons, from 25-40% by unbiased stereological assessment. Further, aged TgF344-AD rats demonstrate marked elevation in the pathogenic tau-associated kinases CDK5 and active GSK-3, and β-amyloid plaque-associated caspase-3+ and TUNEL+ cells. These pathological changes occur with plaque-associated microgliosis and astrogliosis in an age-dependent manner (from 6-27 months). Finally, TgF344-AD rats manifest deficits in both hippocampus-dependent and -independent tests of learning and memory." @default.
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- W2110367560 date "2010-07-01" @default.
- W2110367560 modified "2023-09-27" @default.
- W2110367560 title "S4-03-05: Elucidation of the Amyloid Cascade Hypothesis in the TgF344-AD Rat" @default.
- W2110367560 doi "https://doi.org/10.1016/j.jalz.2010.08.044" @default.
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