ESTROGENS STABILIZE MITOCHONDRIAL-FUNCTION AND PROTECT NEURAL CELLS AGAINST THE PRO-APOPTOTIC ACTION OF MUTANT PRESENILIN-1

MUTATIONS in presenilin-1 (PS-1) account for approximately half the ca ses of autosomal dominant early-onset Alzheimer's disease (AD). Recent data indicate that PS-1 mutations may render neurons vulnerable to ap optosis induced by various insults. We now report that 17 beta-estradi ol, which appears to reduce the risk of sporadic AD, protects cultured PC12 cells expressing mutant PS-1 against apoptosis induced by trophi c factor withdrawal (TFW) and exposure to amyloid beta-peptide 25-35 ( A beta). Estriol also provided significant protection against apoptosi s induced by TFW and A beta, whereas corticosterone was ineffective. 1 7 beta-Estradiol prevented decreases in mitochondrial transmembrane po tential and energy charge/redox state following exposure of cells to T FW and A beta in control cell lines and lines expressing mutant PS-1, suggesting an action in the apoptotic pathway upstream of mitochondria l alterations. A beta caused an increase in mitochondrial reactive oxy gen species which was enhanced by mutant PS-1, and suppressed by 17 be ta-estradiol. The ability of 17 beta-estradiol to preserve mitochondri al function, suppress oxidative stress, and counteract the pro-apoptot ic actions of mutant PS-1 suggests a generalized neuroprotective actio n of estrogens in both sporadic and inherited forms of AD.