Consumers of moderate amounts of ethanol have a lower risk of Alzheimer's dementia than do abstainers. In Alzheimer's disease the brain contains many extracellular plaques composed of amyloid-beta (Abeta), a neurotoxic protein linked to pathogenesis of the disease. Here we report that moderate ethanol preconditioning (20-30 mM for 6 days) of organotypic hippocampal-entorhinal slice cultures prevents Abeta-induced neurotoxicity and apoptosis as measured by media lactate dehydrogenase levels and staining with propidium iodide and Hoechst 33342. With Abeta, as with our previous studies of the neurotoxic HIV-1 protein gp120, moderate ethanol preconditioning may interfere with various glial-mediated neurotoxic responses in the slices to Abeta. In addition, we found that moderate ethanol preconditioning causes an almost 3-fold increase in brain levels of heat shock protein 70 (hsp70), a protective molecular chaperone. Our results suggest possible molecular mechanisms underlying the protective effect of moderate drinking against Alzheimer's dementia.