Stable transfectants of PC12 cells expressing bcl-2 or crmA were generated and tested for their susceptibility to various apoptotic insults. Bcl-2 expression conferred resistance to apoptosis induced by staurosporine and by oxidative insults including hydrogen peroxide and peroxynitrite, but was less effective in inhibition of activation-induced programmed cell death induced by concanavalin A. Concanavalin A-induced apoptosis was abated, however, in cells expressing very high levels of bcl-2. In contrast, cells expressing crmA were protected from concanavalin A-induced apoptosis, but were as susceptible as control cells to apoptosis induced by staurosporine and oxidative insults. Therefore, at least two apoptotic pathways in PC12 cells can be discerned by their differential sensitivity to blockade by bcl-2 and crmA. The ability of beta-amyloid (Abeta) to induce apoptosis in these cells was assessed. CrmA transfectants were protected from apoptosis induced by Abeta1-42, but only cells expressing very high levels of bcl-2 were similarly protected. These results suggest that the apoptotic pathway activated by Abeta1-42 in PC12 cells can be differentiated from the apoptotic pathway activated by oxidative insults. Gene transfer experiments also demonstrated that expression of crmA in primary cultures of hippocampal neurons is protective against cell death induced by Abeta1-42. Together these results support the hypothesis that Abeta-induced apoptosis occurs through activation-induced programmed cell death.