Inhibition of HSP90-dependent telomerase activity in amyloid β-induced apoptosis of cerebral endothelial cells

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Abstract

Although apoptosis induced by amyloid β (Aβ) has been identified, the effect of Aβ on telomerase activity in relation to apoptosis induction remains unclear. In the present study, Aβ1-40 and Aβ25-35, but not Aβ1-16 and Aβ35-25, reduce the viability of primary cerebral endothelial cells (CECs) in accordance with apoptosis induction. Increases in caspase 3 and PARP protein cleavage with reductions of the Bcl-2/Bax protein ratio accompanied by a loss in the mitochondria membrane potential were identified in Aβ1-40 and Aβ25-35-treated CECs. A significant decrease in intracellular telomerase activity by Aβ1-40 and Aβ25-35 was detected; meanwhile, reduced telomerase activity by telomerase reverse transcriptase (TERT) siRNA enhanced the cytotoxic effect of Aβ. The addition of serum might block the Aβ25-35-induced cytotoxic effect via elevated telomerase activity in according with stimulating phospho-AKT protein expression, which was blocked by adding AKT inhibitor LY294002. Decreases in heat shock protein 90 (HSP90) and its client proteins including TERT, AKT, p53, CDK4 were observed in Aβ1-40 and Aβ25-35, but not Aβ1-16 and Aβ35-25, -treated CECs. The knockdown of HSP90 gene expression by HSP90 siRNA significantly inhibits telomerase activity with decreasing TERT protein expression. The application of HSP90 activity inhibitor geldanamycin (GA) and radicicol (RD) potentiates the telomerase inhibition and apoptosis induction of Aβ in CECs. An increase in protein ubiquitination by Aβ25-35, but not Aβ35-25, treatment was examined, and Aβ-inhibited HSP90 and TERT protein expression and telomerase activity was reversed by adding proteasome inhibitor, MG132. Additionally, increased TERT protein ubiquitination by Aβ25-35 was detected in CECs via immunoprecipitation/Western blotting analysis. The data of the present study firstly demonstrates that telomerase inhibition contributes to the apoptosis induction of Aβ in CECs.

Original languageEnglish
Pages (from-to)2041-2051
Number of pages11
JournalJournal of Cellular Physiology
Volume226
Issue number8
DOIs
Publication statusPublished - Aug 2011

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Cell Biology
  • Physiology

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