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Superoxide mediates the cell‐death‐enhancing action of presenilin‐1 mutations
Author(s) -
Guo Qing,
Fu Weiming,
Holtsberg Frederick W.,
Steiner Sheldon M.,
Mattson Mark P.
Publication year - 1999
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/(sici)1097-4547(19990601)56:5<457::aid-jnr2>3.0.co;2-p
Subject(s) - action (physics) , presenilin , programmed cell death , superoxide , neuroscience , chemistry , microbiology and biotechnology , biology , medicine , genetics , apoptosis , biochemistry , disease , alzheimer's disease , physics , enzyme , quantum mechanics
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 β‐peptide 1–42 (Aβ). Mitochondrial calcium accumulation and membrane depolarization following exposure to Aβ 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 Aβ 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. J. Neurosci. Res. 56:457–470, 1999. © 1999 Wiley‐Liss, Inc.