Synapse loss, deposits of amyloid -peptide (A), impaired energy metabolism, and cognitive deficits are defining features of Alzheimer's disease (AD). Estrogen replacement therapy reduces the risk of developing AD in postmenopausal women. Because synapses are likely sites for initiation of neurodegenerative cascades in AD, we tested the hypothesis that estrogens act directly on synapses to suppress oxidative impairment of membrane transport systems. Exposure of rat cortical synaptosomes to A25-35 (A) and FeSO 4 induced membrane lipid peroxidation and impaired the function of the plasma membrane Na ؉ /K ؉ -ATPase, glutamate transporter, and glucose transporter. Pretreatment of synaptosomes with 17-estradiol or estriol largely prevented impairment of Na ؉ /K ؉ -ATPase activity, glutamate transport, and glucose transport; other steroids were relatively ineffective. 17-Estradiol suppressed membrane lipid peroxidation induced by A and FeSO 4 , but did not prevent impairment of membrane transport systems by 4-hydroxynonenal (a toxic lipid peroxidation product), suggesting that an antioxidant property of 17-estradiol was responsible for its protective effects. By suppressing membrane lipid peroxidation in synaptic membranes, estrogens may prevent impairment of transport systems that maintain ion homeostasis and energy metabolism, and thereby forestall excitotoxic synaptic degeneration and neuronal loss in disorders such as AD and ischemic stroke.