Mutant presenilin-1 induces apoptosis and downregulates Akt/PKB

Conrad C. Weihl, Ghanashyam D. Ghadge, Scott G. Kennedy, Nissim Hay, Richard J. Miller, Raymond P. Roos*

*Corresponding author for this work

Research output: Contribution to journalArticle

134 Scopus citations

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 languageEnglish (US)
Pages (from-to)5360-5369
Number of pages10
JournalJournal of Neuroscience
Volume19
Issue number13
DOIs
StatePublished - Jul 1 1999

Keywords

  • Adenoviral vectors
  • Akt/PKB
  • Alzheimer's disease
  • Apoptosis
  • Hippocampal neurons
  • Presenilin

ASJC Scopus subject areas

  • Neuroscience(all)

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