Apoptosis signal-regulating kinase 1 in amyloid β peptide-induced cerebral endothelial cell apoptosis

A pathological hallmark of Alzheimer's disease is accumulation of amyloid-beta peptide ( A beta) in senile plaques. A beta 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 A beta-induced death in primary cultures of murine CECs. A beta 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 ASK1DN and p38MAPK DN, suppressed A beta-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 A beta activates the ASK1-p38MAPK-p53-Bax cascade to cause CEC death in a PP2A-dependent manner.