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The Journal of Neuroscience, July 1, 1999, 19(13):5360-5369

Mutant Presenilin-1 Induces Apoptosis and Downregulates Akt/PKB

Conrad C. Weihl¹, Ghanashyam D. Ghadge³, Scott G. Kennedy⁴, Nissim Hay⁴, Richard J. Miller^{1, 2}, and Raymond P. Roos^{1, 3}

¹ Committee on Neurobiology and Departments of ² Pharmacological and Physiological Sciences and ³ Neurology, University of Chicago, Chicago, Illinois 60637, and ⁴ Department of Molecular Genetics, The University of Illinois at Chicago, Chicago, Illinois 60607

Most early onset cases of familial Alzheimer's disease (AD) are caused by mutations in presenilin-1 (PS1) and presenilin-2 (PS2). These mutations lead to increased -amyloid formation and may induce apoptosis in some model systems. Using primary cultured hippocampal neurons (HNs) and rat pheochromocytoma (PC12) cells transiently transfected with replication-defective recombinant adenoviral vectors expressing wild-type or mutant PS1, we demonstrate that mutant PS1s induce apoptosis, downregulate the survival factor Akt/PKB, and affect several Akt/PKB downstream targets, including glycogen synthase kinase-3 and -catenin. Expression of a constitutively active Akt/PKB rescues HNs from mutant PS1-induced neuronal cell death, suggesting a potential therapeutic target for AD. Downregulation of Akt/PKB may be a mechanism by which mutant PS1 induces apoptosis and may play a role in the pathogenesis of familial AD.

Key words: presenilin; Alzheimer's disease; apoptosis; Akt/PKB; adenoviral vectors; hippocampal neurons

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19135360-10$05.00/0

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