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- W2980436009 abstract "Knock-in (KI) mouse models that endogenously overproduce amyloid-β (Aβ) peptides without non-physiological overexpression of amyloid precursor protein (APP) provide important insights into the pathogenic mechanisms of Alzheimer's disease (AD). In the App-KI mice, three familial AD mutations were introduced in the endogenous mouse App locus to recapitulate Aβ pathology, including the Swedish (NL) mutation that elevates total Aβ production, the Beyreuther/Iberian (F) mutation that increases the Aβ42/Aβ40 ratio, and the Arctic (G) mutation that promotes Aβ aggregation. We previously reported that AppNL-G-F mice, which harbor all three mutations, exhibited emotional alterations before the onset of definitive cognitive deficits. In this study, we aimed to determine whether these mice exhibit cognitive deficits and neurodegeneration at more advanced age. We compared the Morris water maze performance of AppNL-G-F and AppNL mice, which harbor only the Swedish mutation, with that of wild-type (WT) C57BL/6J mice at the age of 24 months. To correlate cognitive deficits and neuroinflammation and synaptic degeneration, we also examined Aβ plaque formation, reactive gliosis and loss of presynaptic markers in these mice. In the Morris water maze, 24-month-old AppNL-G-F/NL-G-F mice exhibited significantly poorer spatial learning than WT mice during the hidden training, but similarly to WT mice during the visible training. Not surprisingly, AppNL-G-F/NL-G-F mice also exhibited spatial memory deficits both 1 and 7 days after the last training. By contrast, 24-month-old AppNL/NL mice had intact spatial learning and memory relative to WT mice. Immunohistochemical analyses revealed that AppNL-G-F/NL-G-F mice developed massive Aβ plaques, reactive gliosis (microgliosis and astrocytosis) and synaptic loss throughout the brain. By contrast, we observed no detectable brain pathology in AppNL/NL mice despite overproduction of human Aβ40 and Aβ42 in their brains. Our results indicate that Aβ plaque formation, followed by sustained neuroinflammation, is necessary for the induction of definitive cognitive deficits and synaptic degeneration in App-KI mouse models of AD. Our data also indicate that introduction of the Swedish mutation alone in endogenous APP is not sufficient to produce either AD-related brain pathology or cognitive deficits in mice." @default.
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- W2980436009 date "2019-07-01" @default.
- W2980436009 modified "2023-09-28" @default.
- W2980436009 title "P4-471: AMYLOID-β PLAQUE FORMATION AND REACTIVE GLIOSIS ARE REQUIRED FOR INDUCTION OF COGNITIVE DEFICITS AND SYNAPTIC DEGENERATION IN APP KNOCK-IN MOUSE MODELS OF ALZHEIMER'S DISEASE" @default.
- W2980436009 doi "https://doi.org/10.1016/j.jalz.2019.08.017" @default.
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