Increased vulnerability of hippocampal neurons from presenilin-1 mutant knock-in mice to amyloid β-peptide toxicity: Central roles of superoxide production and caspase activation

Qing Guo, Lois Sebastian, Bryce L. Sopher, Miles W. Miller, Carol B. Ware, George M. Martin, Mark P. Mattson

Research output: Contribution to journalArticle

Abstract

Many cases of early-onset inherited Alzheimer's disease (AD) are caused by mutations in the presenilin-1 (PS1) gene. Overexpression of PS1 mutations in cultured PC12 cells increases their vulnerability to apoptosis-induced trophic factor withdrawal and oxidative insults. We now report that primary hippocampal neurons from PS1 mutant knock-in mice, which express the human PS1M146V mutation at normal levels, exhibit increased vulnerability to amyloid β-peptide toxicity. The endangering action of mutant PS1 was associated with increased superoxide production, mitochondrial membrane depolarization, and caspase activation. The peroxynitrite-scavenging antioxidant uric acid and the caspase inhibitor benzyloxycarbonyl-Val-Ala- Asp-fluoromethyl ketone protected hippocampal neurons expressing mutant PS1 against cell death induced by amyloid β-peptide. Increased oxidative stress may contribute to the pathogenic action of PS1 mutations, and antioxidants may counteract the adverse property of such AD-linked mutations.

Original languageEnglish (US)
Pages (from-to)1019-1029
Number of pages11
JournalJournal of Neurochemistry
Volume72
Issue number3
DOIs
StatePublished - 1999
Externally publishedYes

Keywords

  • Alzheimer's disease
  • Mitochondrial transmembrane potential
  • Peroxynitrite
  • Uric acid

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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