Concomitant degradation of β-catenin and GSK-3β potently contributes to glutamate-induced neurotoxicity in rat hippocampal slice cultures

Jee Hee Lee, Eun Ok Lee, Ji Hee Lee Kang, Young Hae Chong

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

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 Ca2+ 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.

Original languageEnglish
Pages (from-to)1066-1077
Number of pages12
JournalJournal of Neurochemistry
Volume106
Issue number3
DOIs
StatePublished - Aug 2008

Keywords

  • β-catenin
  • Alzheimer's disease
  • Ca influx
  • Calpain-1
  • Glutamate
  • GSK-3β

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