Mutant presenilin-1 induces apoptosis and downregulates Akt PKB

Most early onset cases of familial Alzheimer's disease (AD) are caused by m utations in presenilin-1 (PS1) and presenilin-2 (PS2). These mutations lead to increased beta-amyloid formation and may induce apoptosis in some model systems. Using primary cultured hippocampal neurons (HNs) and rat pheochro mocytoma (PC12) cells transiently transfected with replication-defective re combinant adenoviral vectors expressing wild-type or mutant PS1, we demonst rate that mutant PS1s induce apoptosis, downregulate the survival factor Ak t/PKB, and affect several Akt/PKB downstream targets, including glycogen sy nthase kinase-3 beta and beta-catenin. Expression of a constitutively activ e Akt/PKB rescues HNs from mutant PS1-induced neuronal cell death, suggesti ng 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 th e pathogenesis of familial AD.