Mutations in presenilin-1 (PS-1) account for approximately half the cases of autosomal dominant early-onset Alzheimer's disease (AD). Recent data indicate that PS-1 mutations may render neurons vulnerable to apoptosis induced by various insults. We now report that 17beta-estradiol, which appears to reduce the risk of sporadic AD, protects cultured PC12 cells expressing mutant PS-1 against apoptosis induced by trophic factor withdrawal (TFW) and exposure to amyloid beta-peptide 25-35 (Abeta). Estriol also provided significant protection against apoptosis induced by TFW and Abeta, whereas corticosterone was ineffective. 17beta-Estradiol prevented decreases in mitochondrial transmembrane potential and energy charge/redox state following exposure of cells to TFW and Abeta in control cell lines and lines expressing mutant PS-1, suggesting an action in the apoptotic pathway upstream of mitochondrial alterations. Abeta caused an increase in mitochondrial reactive oxygen species which was enhanced by mutant PS-1, and suppressed by 17beta-estradiol. The ability of 17beta-estradiol to preserve mitochondrial function, suppress oxidative stress, and counteract the pro-apoptotic actions of mutant PS-1 suggests a generalized neuroprotective action of estrogens in both sporadic and inherited forms of AD.