The 26-kDa protein encoded by the bcl-2 gene is a regulator of cell survival and blocks cell death induced by numerous stimuli. Amyloid beta protein (ABP) and glutamate are believed to play important roles in the neuronal cell death that occurs in Alzheimer's disease and stroke, respectively. Glutamate induces apoptosis in some neuronal cell systems, but it remains controversial whether ABP-mediated cell death occurs through apoptosis or necrosis. To further explore the pathways for cell death that are activated by these neurotoxins, we examined the effects of elevated levels of the p26-Bcl-2 protein on the susceptibility of neuronal cell lines to killing by glutamate and ABP. Gene transfer methods were used to elevate p26-Bcl-2 protein levels in the rat nerve lines PC-12 and B50 and the human neuroblastoma IMR-5. Bcl-2 protected all 3 cell lines from glutamate induced cell death but had no effect on killing mediated by ABP.