Abstract
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 β-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-3β and β-catenin. Expression of a constitutively active Akt/PKB rescues HNs from mutant PSI-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.
Original language | English (US) |
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Pages (from-to) | 5360-5369 |
Number of pages | 10 |
Journal | Journal of Neuroscience |
Volume | 19 |
Issue number | 13 |
DOIs | |
State | Published - Jul 1 1999 |
Keywords
- Adenoviral vectors
- Akt/PKB
- Alzheimer's disease
- Apoptosis
- Hippocampal neurons
- Presenilin
ASJC Scopus subject areas
- General Neuroscience