67 引文 斯高帕斯(Scopus)

摘要

Apathological hallmark of Alzheimer's disease is accumulation of amyloid-β peptide (Aβ) in senile plaques. Aβ has also been implicated in vascular degeneration in cerebral amyloid angiopathy because of its cytotoxic effects on non-neuronal cells, including cerebral endothelial cells (CECs). We explore the role of apoptosis signal-regulating kinase 1 (ASK1) in Aβ-induced death in primary cultures of murine CECs. Aβ induced ASK1 dephosphorylation, which could be prevented by selective inhibition of protein phosphatase 2A (PP2A) but not PP2B. ASK1 dephosphorylation resulted in its dissociation from 14-3-3. ASK1, released from 14-3-3 inhibition, activated p38 mitogen-activated protein kinase (p38MAPK), leading to p53 phosphorylation. p53, a proapoptotic transcription factor, in turn transactivated the expression of Bax, a proapoptotic protein. Transfection with various dominant-negative mutants (DNs), including ASK1 DN and p38MAPK DN, suppressed Aβ-induced p38MAPK activation, p53 phosphorylation, and Bax upregulation and partially prevented CEC death. Bax knockdown using a bax small interfering RNA strategy also reduced Bax expression and subsequent CEC death. These results suggest that Aβ activates the ASK1-p38MAPK-p53-Bax cascade to cause CEC death in a PP2A-dependent manner.
原文英語
頁(從 - 到)5719-5729
頁數11
期刊Journal of Neuroscience
27
發行號21
DOIs
出版狀態已發佈 - 五月 23 2007

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)

指紋 深入研究「Apoptosis signal-regulating kinase 1 in amyloid β peptide-induced cerebral endothelial cell apoptosis」主題。共同形成了獨特的指紋。

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