Familial Alzheimer's disease (FAD) mutant forms of presenilin 1 (PS1) and 2 have been shown to sensitize cells to apoptotic cell death. Here we explore the effects of FAD mutant forms of PS1 on caspase activation during apoptosis. We show that caspase activation leads to increased generation of alternative C-terminal fragments (CTFs) from mutant as compared to wild-type (wt) PS1. For this purpose, very low expression levels of wt, A246E, L286V, and deltaE10 FAD mutant PS1 proteins in stably transfected human H4 neuroglioma cells were used to avoid artifactual induction of spontaneous apoptosis due to overexpression of PS1. Staurosporine treatment of these cells resulted in increased cell death and up to a 10-fold increase in caspase-3 activation in mutant versus wt PS1-expressing cell lines. Correspondingly, relative levels of caspase-cleaved PS1 CTFs were increased by five- to sixfold in the FAD mutant versus wt PS1 cells. Elevated caspase activation and caspase cleavage of FAD mutant PS1 suggest the possibility of either a direct proapoptotic effect of mutant PS1 or interference of mutant PS1 with antiapoptotic effects of wt PS1.