Apoptosis signal-regulating kinase 1 in amyloid beta peptide-induced cerebral endothelial cell apoptosis.
A pathological hallmark of Alzheimer's disease is accumulation of amyloid-beta peptide (Abeta) in senile plaques. Abeta 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 Abeta-induced death in primary cultures of murine CECs. Abeta 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 Abeta-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 Abeta activates the ASK1-p38MAPK-p53-Bax cascade to cause CEC death in a PP2A-dependent manner.
Hsu
Ming-Jen
MJ
Graduate Institute of Medical Sciences, Taipei Medical University, Taipei 110, Taiwan.
Hsu
Chung Y
CY
Chen
Bing-Chang
BC
Chen
Mei-Chieh
MC
Ou
George
G
Lin
Chien-Huang
CH
D016229:Amyloid beta-Peptides / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D042783:Endothelial Cells / Q000201:enzymology* / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics / Q000378:metabolism
D016229:Amyloid beta-Peptides; D048308:Mitogen-Activated Protein Kinase 14; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse