Treatment of rat pheochromocytoma cells(PC12)cells with β-amyloid peptide-(1-42)for 24h induced a concentration-dependent decrease in cellular redox activity in the dose range of 1 to 20μM. These effects were markedly attenuated by pretreatment with 2 mM LiCl for 7 days, whereas 1-day pretreatment was ineffective. Measurements of live and dead cells by double-staining with fluorescein diacetate and propidium iodide, respectively revealed that protracted lithium pretreatment attenuated PC 12 cell death induced by β-amyloid-(1-42) and cerebellar granule cell death induced by β-amyloid-(25-35). Preceding PC 12 cell death, β-amyloid peptide elicited a slight decrease in protein levels of Bcl-2. Conversely, 7-day pretreatment with lithium resulted in an approximate doubling of Bcl-2 protein levels in cells treated with or without β-amyloid peptide-(1-42). Lithium-induced Bcl-2 upregulation was temporally associated with the cytoprotective effects of this drug. Thus, lithium protection against β-amyloid peptide neurotoxicity might involve Bcl-2 overexpression, and lithium treatment for Alzheimer’s disease should be reexamined.