Staurosporine-induced activation of caspase-3 is potentiated by presenilin1 familial Alzheimer's disease mutations in human neuroglioma cells

Familial Alzheimer's disease (FAD) mutant forms of presenilin I (PS1) and 2 have been shown to sensitize cells to apoptotic cell death. Here we explor e the effects of FAD mutant forms of PS1 on caspase activation during apopt osis, We show that caspase activation leads to increased generation of alte rnative C-terminal fragments (CTFs) from mutant as compared to wild-type (w t) PS1. For this purpose, very low expression levels of wt, A246E, L286V, a nd Delta E10 FAD mutant PS1 proteins in stably transfected human H4 neurogl ioma cells were used to avoid artifactual induction of spontaneous apoptosi s due to overexpression of PS1, Staurosporine treatment of these cells resu lted in increased cell death and up to a 10-fold increase in caspase-3 acti vation in mutant versus wt PS1-expressing cell lines. Correspondingly, rela tive levels of caspase-cleaved PS1 CTFs were increased by five- to sixfold in the FAD mutant versus wt PS1 cells. Elevated caspase activation and casp ase cleavage of FAD mutant PS1 suggest the possibility of either a direct p roapoptotic effect of mutant PS1 or interference of mutant PS1 with antiapo ptotic effects of wt PS1.