25-35 alters Akt activity, resulting in Bad translocation and mitochondrial dysfunction in cerebrovascular endothelial cells

Ke Jie Yin, Jin Moo Lee, Hong Chen, Jan Xu, Chung Y. Hsu

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

The amyloid-beta peptide (Aβ) induces apoptosis in cerebrovascular endothelial cells (CECs), contributing to the pathogenesis of cerebral amyloid angiopathy. We have previously shown that Aβ induces apoptosis in CECs. In the present study, we report that Aβ25-35-induced CEC apoptosis involves the inactivation of Akt, a signaling kinase important in maintaining cell viability. Akt prevents the activation of death-signaling events by facilitating the inactivation of proapoptotic proteins such as Bad. We applied three strategies to show that Aβ25-35 inactivation of Akt is causally related to Aβ25-35-induced CEC death by preventing Bad activation and subsequent mitochondrial dysfunction (reflected by the release of endonuclease G and Smac, two proapoptotic intermembranous proteins of the mitochondria). Wortmannin, a PI3-kinase inhibitor, enhanced Aβ25-35-induced Bad activation, mitochondrial dysfunction and CEC death. Enhancement of Akt activity by a Tat-Akt fusion protein, or by viral gene transfer of a constitutively active mutant of akt, reduced Bad activation, mitochondrial dysfunction, and CEC death. Using a siRNA strategy to knock down the bad gene, we showed that Bad activation is causally related to Aβ25-35-induced mitochondrial dysfunction and CEC death. Together, these results establish that the Akt-Bad cascade is altered by Aβ25-35, resulting in CEC apoptosis.

Original languageEnglish
Pages (from-to)1445-1455
Number of pages11
JournalJournal of Cerebral Blood Flow and Metabolism
Volume25
Issue number11
DOIs
Publication statusPublished - Nov 2005

Keywords

  • Amyloid angiopathy
  • Apoptosis
  • Endonuclease G
  • Smac
  • Tat-Akt

ASJC Scopus subject areas

  • Endocrinology
  • Neuroscience(all)
  • Endocrinology, Diabetes and Metabolism

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