Estrogen-replacement therapy has been associated with a reduced incidence of Alzheimer's disease (AD) and improved cognition in several small open clinical trials. We assessed the possibility that estrogens may reduce toxicity of beta-amyloid (A beta) by testing the effects of beta-estradiol on the toxicity of the neurotoxic fragment of beta-amyloid (A beta 25-35) in SK-N-SH neuroblastoma cells. A beta 25-35 caused a dose-dependent death in SK-N-SH cells with a LD50 of 28.9 muM. In cultures simultaneously exposed to 20 muM A beta and 17 beta-estradiol (2 nM). A beta-induced toxicity was reduced by 83 and 51% in two separate studies. Further studies show that 0.2 nM 17 beta-estradiol was as effective as the 2 nM concentration. 17 alpha-Estradiol (2 nM) conferred neuroprotection equivalent to that of 17 beta-estradiol. These data support the hypothesis that estrogens reduce beta-amyloid toxicity and this may help explain the beneficial effects of estrogens in AD.