beta-Amyloid((1-40))-induced apoptosis of cultured cortical neurones involves calpain-mediated cleavage of poly-ADP-ribose polymerase. beta-Amyloid protein is thought to contribute to the pathophysiology of Alzheimer's disease by inducing neuronal apoptosis. Our previous work has demonstrated that beta-amyloid activates voltage-dependent Ca(2+) channels in the cortex, resulting in an increase in intracellular Ca(2+) concentration. Calpain is a Ca(2+)-dependent neutral protease which becomes activated following alterations in intracellular Ca(2+) homeostasis. In this study we have demonstrated that beta-amyloid increases calpain activity in cultured cortical neurones in a time-dependent manner. Use of the cell-permeable calpain inhibitor, MDL 28170, has identified cleavage of the DNA-repair enzyme, poly-ADP-ribose polymerase, and DNA fragmentation as downstream consequences of calpain activation. Thus, we propose that the stimulatory effect of beta-amyloid on Ca(2+) influx triggers calpain-mediated DNA fragmentation in cultured cortical neurones.