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The Journal of Neuroscience, May 23, 2007, 27(21):5719-5729; doi:10.1523/JNEUROSCI.1874-06.2007

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Neurobiology of Disease
Apoptosis Signal-Regulating Kinase 1 in Amyloid ß Peptide-Induced Cerebral Endothelial Cell Apoptosis

Ming-Jen Hsu,^1,5 Chung Y. Hsu,^2,5 Bing-Chang Chen,³ Mei-Chieh Chen,⁴ George Ou,⁶ and Chien-Huang Lin^1,5

¹Graduate Institute of Medical Sciences, ²Department of Neurology and Chi-Chin Huang Stroke Research Center, ³School of Respiratory Therapy, ⁴Department of Microbiology and Immunology, College of Medicine, and ⁵Topnotch Stroke Research Center, Taipei Medical University, Taipei 110, Taiwan, and ⁶Simon Fraser University, Burnaby, British Columbia, Canada V5A 1S6

Correspondence should be addressed to Dr. Chien-Huang Lin, Graduate Institute of Medical Science, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110, Taiwan. Email: chlin{at}tmu.edu.tw

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

Key words: angiopathy; ASK1; Bax; cerebrovascular diseases; p38 mitogen-activated protein kinase; p38MAPK; p53

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Received May 2, 2006; revised April 19, 2007; accepted April 21, 2007.

Correspondence should be addressed to Dr. Chien-Huang Lin, Graduate Institute of Medical Science, College of Medicine, Taipei Medical University, 250 Wu-Hsing Street, Taipei 110, Taiwan. Email: chlin{at}tmu.edu.tw

This article has been cited by other articles:

				C.-C. Yu, M.-J. Hsu, M.-L. Kuo, R. F.-C. Chen, M.-C. Chen, K.-J. Bai, M.-C. Yu, B.-C. Chen, and C.-H. Lin Thrombin-Induced Connective Tissue Growth Factor Expression in Human Lung Fibroblasts Requires the ASK1/JNK/AP-1 Pathway J. Immunol., June 15, 2009; 182(12): 7916 - 7927. [Abstract] [Full Text] [PDF]

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