beta-Amyloid (A beta) is a 39-42 amino acid that is the primary component of plaques in Alzheimer's disease (AD). Previous studies from our laboratory and others have shown that A beta induces neurodegeneration via apoptosis in vitro, suggesting that A beta may also initiate an apoptotic pathway of cell death in AD. Apoptosis has been suggested to proceed by a gene-directed program in several systems. Accordingly, we have investigated whether A beta-mediated apoptosis is associated with the induction of genes that may regulate or play a role in cell death in vitro. Immediate early genes (IEGs) respond to cellular stimuli and participate in cellular signaling pathways. The protein products of some IEGs, e.g., c-jun, are capable of forming dimers and acting as transcriptional regulatory proteins, and have been implicated in apoptosis in both nonneuronal and neuronal cells. In this study, we report a selective and abnormally sustained induction of c-Jun in cultured hippocampal neurons treated with A beta. In addition, we describe the lack of induction of c-Jun in neurons that are relatively resistant to A beta-mediated toxicity, and a correspondence between immunoreactivity for c-Jun and changes in nuclear morphology that are indicative of apoptosis. These data demonstrate that c-Jun is induced in cultured neurons that undergo A beta-mediated apoptosis and suggest that c-Jun may participate in a cell death program in these neurons.