Superoxide mediates the cell-death-enhancing action of presenilin-1 mutations.

TitleSuperoxide mediates the cell-death-enhancing action of presenilin-1 mutations.
Publication TypeJournal Article
Year of Publication1999
JournalJournal of neuroscience research
Volume56
Issue5
Pagination457-70
Date Published1999
ISSN0360-4012
Abstract

The mechanism whereby mutations in the presenilin-1 (PS-1) gene on chromosome 14 cause early-onset inherited Alzheimer's disease are unknown. We report that PC6 neural cells (a subclone of PC12 cells) expressing PS-1 mutations (M146V and L286V) exhibit increased superoxide production, nitrotyrosine accumulation, and membrane lipid peroxidation following exposure to amyloid beta-peptide 1-42 (Abeta). Mitochondrial calcium accumulation and membrane depolarization following exposure to Abeta were enhanced in cells expressing mutant PS-1. Overexpression of mitochondrial Mn-SOD greatly reduced superoxide production, nitrotyrosine formation, membrane lipid peroxidation, intramitochondrial calcium accumulation, and membrane depolarization following exposure to Abeta and conferred resistance to the apoptosis-enhancing action of the PS-1 mutations. Nitric oxide synthase inhibitors and the peroxynitrite scavenger uric acid blocked the apoptosis-enhancing action of PS-1 mutations. The data suggest pivotal roles for superoxide production and resulting peroxynitrite formation in the pathogenic mechanism of PS-1 mutations.

URLhttp://onlinelibrary.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0360-4012&date=1999&volume=56&issue=5&spage=457
DOI10.1002/(SICI)1097-4547(19990601)56:5<457::AID-JNR2>3.0.CO;2-P
Short TitleJ Neurosci Res
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