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• W1973063876 abstract "Abstract Increasingly, published evidence links glutamate with the pathogenesis of Alzheimer’s disease. We investigated the molecular mechanism underlying glutamate‐induced neurotoxicity in hippocampus, which is primarily linked to cognitive dysfunction in Alzheimer’s disease. Acute exposure of rat hippocampal slices to glutamate significantly induced cell death, as determined by media lactate dehydrogenase levels and PI staining. Moreover, this was accompanied by Ca 2+ influx and calpain‐1 activation, as confirmed by the proteolytic pattern of spectrin. Notably, glutamate‐induced calpain‐1 activation decreased the level of β‐catenin, and this process appeared to be independent of glycogen synthase kinase 3beta (GSK‐3β), since glutamate also led to loss of GSK‐3β. Calpeptin, a calpain inhibitor, attenuated the glutamate‐mediated degradations of spectrin, synaptophysin, and β‐catenin except GSK‐3β and modestly increased cell survival. In contrast, the NMDA receptor antagonist 2‐amino‐5‐phosphonopentanoic acid (APV) effectively reduced all glutamate‐evoked responses, i.e., the breakdowns of spectrin, synaptophysin, β‐catenin and GSK‐3β, and cell death. Pharmacological studies and in vitro calpain‐1 proteolysis confirmed that in the glutamate‐treated hippocampus, calpain‐1‐mediated decrease of β‐catenin could occur independently of GSK‐3β and of proteasome, and that GSK‐3β degradation is independent of calpain‐1. These findings together provide the first direct evidence that glutamate promotes the down‐regulations of β‐catenin and GSK‐3β, which potently contribute to neurotoxicity in hippocampus during excitotoxic cell death, and a molecular basis for the protection afforded by calpeptin and APV from the neurotoxic effect of glutamate." @default.
• W1973063876 created "2016-06-24" @default.
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• W1973063876 date "2008-07-15" @default.
• W1973063876 modified "2023-10-16" @default.
• W1973063876 title "Concomitant degradation of -catenin and GSK-3 potently contributes to glutamate-induced neurotoxicity in rat hippocampal slice cultures" @default.
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• W1973063876 doi "https://doi.org/10.1111/j.1471-4159.2008.05444.x" @default.
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