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Arterioscler Thromb Vasc Biol. 2014 Mar;34(3):616-25. doi: 10.1161/ATVBAHA.113.302440. Epub 2013 Dec 26.

Apoptosis signal-regulating kinase 1 is a novel target molecule for cognitive impairment induced by chronic cerebral hypoperfusion.

Author information

1
From the Department of Pharmacology and Molecular Therapeutics (K.T., N.K., K.U., Y.H., K.K., T.K., D.S., M.J.M., T.N., S.K.-M.) and Department of Cardiovascular Medicine, Faculty of Life Science (K.T., H.O.), Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan; Research Fellowship of the Japan Society for the Promotion of Science, Tokyo, Japan (K.T.); Department of Cardiovascular Clinical and Translational Research, Kumamoto University Hospital, Kumamoto, Japan (O.Y.); Department of Neurology, Graduate School of Medicine, Mie University, Tsu, Japan (H.T.); and Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, and Global Center of Excellence (GCOE) Program, The University of Tokyo, Tokyo, Japan (H.I.).

Abstract

OBJECTIVE:

There are currently no specific strategies for the treatment or prevention of vascular dementia. White matter lesions, a common pathology in cerebral small vessel disease, are a major cause of vascular dementia. We investigated whether apoptosis signal-regulating kinase 1 (ASK1) might be a key molecule in cerebral hypoperfusion, associated with blood-brain barrier breakdown and white matter lesions.

APPROACH AND RESULTS:

A mouse model of cognitive impairment was developed by inducing chronic cerebral hypoperfusion in white matter including the corpus callosum via bilateral common carotid artery stenosis (BCAS) surgery. BCAS-induced white matter lesions caused cognitive decline in C57BL/6J (wild-type) mice but not in ASK1-deficient (ASK1(-/-)) mice. Phosphorylated ASK1 increased in wild-type mouse brains, and phosphorylated p38 and tumor necrosis factor-α expression increased in corpus callosum cerebral endothelial cells after BCAS in wild-type mice but not in ASK1(-/-) mice. BCAS decreased claudin-5 expression and disrupted blood-brain barrier in the corpus callosum of wild-type but not ASK1(-/-) mice. Cerebral nitrotyrosine was increased in wild-type and ASK1(-/-) BCAS mice. Cerebral phosphorylated ASK1 did not increase in wild-type mice treated with NADPH-oxidase inhibitor. A p38 inhibitor and NADPH-oxidase inhibitor mimicked the protective effect of ASK1 deficiency against cognitive impairment. Specific ASK1 inhibitor prevented cognitive decline in BCAS mice. In vitro oxygen-glucose deprivation and tumor necrosis factor-α stimulation caused the disruption of endothelial tight junctions from wild-type mice but not ASK1(-/-) mice.

CONCLUSIONS:

Oxidative stress-ASK1-p38 cascade plays a role in the pathogenesis of cognitive impairment, through blood-brain barrier breakdown via the disruption of endothelial tight junctions. ASK1 might be a promising therapeutic target for chronic cerebral hypoperfusion-induced cognitive impairment.

KEYWORDS:

ASK1 protein, mouse; blood–brain barrier; dementia, vascular

PMID:
24371084
DOI:
10.1161/ATVBAHA.113.302440
[Indexed for MEDLINE]
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