Presenilins are the catalytic subunit of the large gamma-secretase complex, that promotes intramembranous proteolysis of the beta-amyloid precursor protein (APP), resulting in the production of beta-amyloid (A beta). Mutant presenilin causes early-onset familial Alzheimer's disease (FAD), is related to abnormal Ca(2+) signaling, and render cells vulnerable to cell death. In the present study, we demonstrated that Ca(2+)-mediated cell death is functionally associated with gamma-secretase activity. We found that gamma-secretase activity was elevated during Ca(2+)-mediated cell death. Using selective gamma-secretase inhibitors, we examined the role of gamma-secretase in cell death triggered by increased intracellular Ca(2+). Indeed, treatment with the selective gamma-secretase inhibitors, compound E, DAPT, or L-685.458 significantly decreased Ca(2+)-triggered cell death with that of the controls, but did not affect staurosporin or tunicamycin-mediated cell death. These results implicate the role of gamma-secretase activity in Ca(2+)-mediated cell death.