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© The Rockefeller University Press, 0021-9525/1999//1351 $5.00
The Journal of Cell Biology, Volume 146, Number 6, , 1999 1351-1364

Original Article

Apoptotic Activities of Wild-Type and Alzheimer's Disease-Related Mutant Presenilins in Drosophila melanogaster



Yihong Yea and Mark E. Fortinia

a Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
Department of Genetics, Stellar-Chance Laboratories 709C, 422 Curie Boulevard, University of Pennsylvania School of Medicine, Philadelphia, PA 19104.(215) 573-9411(215) 573-6446

fortini{at}mail.med.upenn.edu

Mutant human presenilins cause early-onset familial Alzheimer's disease and render cells susceptible to apoptosis in cultured cell models. We show that loss of presenilin function in Drosophila melanogaster increases levels of apoptosis in developing tissues. Moreover, overexpression of presenilin causes apoptotic and neurogenic phenotypes resembling those of Presenilin loss-of-function mutants, suggesting that presenilin exerts a dominant negative effect when expressed at high levels. In Drosophila S2 cells, Psn overexpression leads to reduced Notch receptor synthesis affecting levels of the intact ~300-kD precursor and its ~120-kD processed COOH-terminal derivatives. Presenilin-induced apoptosis is cell autonomous and can be blocked by constitutive Notch activation, suggesting that the increased cell death is due to a developmental mechanism that eliminates improperly specified cell types. We describe a genetic model in which the apoptotic activities of wild-type and mutant presenilins can be assessed, and we find that Alzheimer's disease-linked mutant presenilins are less effective at inducing apoptosis than wild-type presenilin.

Key Words: presenilin • Alzheimer's disease • apoptosis • Notch signaling • neurodegeneration

© 1999 The Rockefeller University Press

1.used in this paper: Aβ40, 40-amino acid amyloid peptide; Aβ42, 42-amino acid amyloid peptide; APP, amyloid precursor protein; DIAP, Drosophila inhibitor of apoptosis protein; PS1, presenilin 1; PS2, presenilin 2


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