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© The Rockefeller University Press, 0021-9525/1997//485 $5.00
The Journal of Cell Biology, Volume 139, Number 2, , 1997 485-495

Article

Increased Apoptosis Arising from Increased Expression of the Alzheimer's Disease–associated Presenilin-2 Mutation (N141I)



Susan Janicki and Mervyn J. Monteiro

Medical Biotechnology Center of the University of Maryland Biotechnology Institute and Departments of Molecular Biology and Biophysics, Neurology, and Human Genetics, Baltimore, Maryland 21201

Mutations in the genes for presenilin 1 and 2 (PS-1 and PS-2) have been linked to development of early-onset Alzheimer's disease (AD). As neither the normal function of either presenilin is known nor why mutations cause disease, we examined the properties of wild-type, truncated, and mutant PS-2 upon expression in HeLa cells. Although HeLa cells are strongly predisposed to continued mitosis, expression of PS-2 induced 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 fluorescent 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 accumulation. Expression of the presenilins in several other cell lines and transgenic mice has been accompanied by rapid protein cleavage without the induction of cell death. In contrast, PS-2 expressed in HeLa cells was not cleaved, and cell death occurred. We hypothesize that full-length but not cleaved PS-2 may be important in the regulation or induction of apoptosis.

Abbreviations used in this paper: aa, amino acid(s); AD, Alzheimer's disease; βAPP, β-amyloid precursor protein gene; CMV, cytomegalovirus; DAPI, 4'6-diamidino-2-phenylindole; GST, glutathione-S-transferase; PS-1 and -2, presenilin 1 and 2; TMD, transmembrane domain.

Address all correspondence to Mervyn J. Monteiro, Ph.D., University of Maryland Biotechnology Institute, Room N352, 725 West Lombard Street, Baltimore, MD 21201. Tel.: (410) 706-8132. Fax: (410) 706-1732.


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