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 language | English (US) |
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Pages (from-to) | 1019-1029 |
Number of pages | 11 |
Journal | Journal of Neurochemistry |
Volume | 72 |
Issue number | 3 |
DOIs | |
State | Published - 1999 |
Externally published | Yes |
Keywords
- Alzheimer's disease
- Mitochondrial transmembrane potential
- Peroxynitrite
- Uric acid
ASJC Scopus subject areas
- Biochemistry
- Cellular and Molecular Neuroscience