Clinical studies have shown that estrogen replacement therapy is associated with reduced risk of Alzheimer's disease (AD). We tested whether or not estrogen blocks neurotoxic effects of beta-amyloid (1-42) (A beta1-42) on cultured B103 cells. A beta1-42 (1 microM) induced typical necrotic cell death, as revealed by light and electron microscopic examinations. Co-administration of estrogen not only blocked A beta1-42 toxicity to a large degree, but also enhanced neurite extension. Pretreatment with estrogen was even more effective in blocking A beta1-42 toxicity. When added 18 h after the beginning of A beta1-42 treatment, estrogen was still effective in halting the progress of cell death and enhancing neurite extension. The protection against A beta1-42-induced neuronal death by estrogen was unlikely due to a blockade of lipid peroxidation injury, since estrogen completely failed to attenuate ferrous chloride-induced cell death. These results demonstrate that estrogen blocks A beta1-42-induced neurotoxicity and enhances neurite extension on B103 cells, both of which may well be underlying mechanisms of beneficial effects of estrogen in AD.