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.
|Number of pages||10|
|Journal||Journal of Neuroscience|
|State||Published - Jul 1 1999|
- Adenoviral vectors
- Alzheimer's disease
- Hippocampal neurons