INCREASED APOPTOSIS ARISING FROM INCREASED EXPRESSION OF THE ALZHEIMERS-DISEASE-ASSOCIATED PRESENILIN-2 MUTATION (N141I)

Mutations in the genes for presenilin 1 and 2 (PS-1 and PS-2) have bee n linked to development of early-onset Alzheimer's disease (AD). As ne ither the normal function of either presenilin is known nor why mutati ons cause disease, we examined the properties of wild-type, truncated, and mutant PS-2 upon expression in HeLa cells. Although HeLa cells ar e strongly predisposed to continued mitosis, expression of PS-2 induce d programmed cell death (apoptosis). Direct evidence for apoptosis was obtained by double staining for terminal deoxynucleotide transferase nick end labeling (TUNEL) and PS-2 expression and by following green f luorescent protein-tagged PS-2 over time. Deletion analysis indicates that as little as 166 NH2-terminal residues of PS-2 are sufficient for endoplasmic reticulum (ER) localization and apoptosis. Moreover, the AD-associated PS-2 missense mutation (N141I) more efficiently induced cell death compared to wild-type PS-2 despite lower mutant protein acc umulation. Expression of the presenilins in several other cell lines a nd transgenic mice has been accompanied by rapid protein cleavage with out the induction of cell death. In contrast, PS-2 expressed in HeLa c ells was not cleaved, and cell death occurred. We hypothesize that ful l-length but not cleaved PS-2 may be important in the regulation or in duction of apoptosis.