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.

Original languageEnglish
Pages (from-to)5719-5729
Number of pages11
JournalJournal of Neuroscience
Issue number21
Publication statusPublished - May 23 2007


  • Angiopathy
  • ASK1
  • Bax
  • Cerebrovascular diseases
  • p38 mitogen-activated protein kinase
  • p38MAPK
  • p53

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)


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