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

Many cases of early-onset inherited Alzheimer's disease (AD) are caused by mutations in the presenilin-1 (PSI) gene. Overexpression of PSI 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 beta-peptide toxicity. The endangering action of mutant PSI 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 PSI against cell death induced by amyloid beta-peptide. Increased oxidative stress may contribute to the pathogenic action of PSI mutations, and antioxidants may counteract the adverse property of such AD-linked mutations.