In light of recent evidence implicating the upregulation of outward K+ current in mediating several forms of neuronal apoptosis, we tested the hypothesis that such an upregulation might specifically contribute to the pathogenesis of beta-amyloid peptide (A beta)-induced neuronal death. Exposure to A beta fragment 25-35 (20 microM) or 1-42 (20 microM) enhanced the delayed rectifier K+ current IK, shifting its activation voltage relationship toward hyperpolarized levels and increasing maximal conductance, but did not affect the transient K+ current IA or charybdotoxin-sensitive BK current. Reducing IK by adding the channel blocker tetraethylammonium (TEA, 5 mM) or raising extracellular K+ to 25 mM attenuated A beta-induced neuronal death, even in the presence of nifedipine or gadolinium to block associated increases in Ca2+ influx. The IA blocker 4-aminopyridine (4-AP, 5 mM) and the CI- channel blocker anthracene-9-carboxylic acid (ACA, 500 microM) were not neuroprotective. These data raise the intriguing possibility that manipulations aimed at reducing outward K+ current may provide an approach to reducing neuronal degeneration in patients with Alzheimer's disease.