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

The mechanism whereby mutations in the presenilin-1 (PS-1) gene on chromoso me 14 cause early-onset inherited Alzheimer's disease are unknown, We repor t that PC6 neural cells (a subclone of PC12 cells) expressing PS-1 mutation s (M146V and L286V) exhibit increased superoxide production, nitrotyrosine accumulation, and membrane lipid peroxidation following exposure to amyloid beta-peptide 1-42 (A beta). Mitochondrial calcium accumulation and membran e depolarization following exposure to A beta were enhanced in cells expres sing mutant PS-1, Overexpression of mitochondrial Mn-SOD greatly reduced su peroxide production, nitrotyrosine formation, membrane lipid peroxidation, intramitochondrial calcium accumulation, and membrane depolarization follow ing exposure to A beta and conferred resistance to the apoptosis-enhancing action of the PS-1 mutations. Nitric oxide synthase inhibitors and the pero xynitrite scavenger uric acid blocked the apoptosis-enhancing action of PS- 1 mutations, The data suggest pivotal roles for superoxide production and r esulting peroxynitrite formation in the pathogenic mechanism of PS-1 mutati ons. (C) 1999 Wiley-Liss, Inc.