Apoptosis Signal- Regulating Kinase 1 Is a Novel Target Molecule for Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion

作者：Toyama Kensuke; Koibuchi Nobutaka; Uekawa Ken; Hasegawa Yu; Kataoka Keiichiro; Katayama Tetsuji; Sueta Daisuke; Ma Ming Jie; Nakagawa Takashi; Yasuda Osamu; Tomimoto Hidekazu; Ichijo Hidenori; Ogawa Hisao; Kim Mitsuyama Shokei^*

来源：Arteriosclerosis, Thrombosis, and Vascular Biology, 2014, 34(3): 616-625.

DOI：10.1161/ATVBAHA.113.302440

• ASK1 protein
• mouse
• blood-brain barrier
• dementia
• vascular

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. %26lt;br%26gt;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- 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- stimulation caused the disruption of endothelial tight junctions from wild-type mice but not ASK1(-/-) mice. %26lt;br%26gt;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.

• 出版日期2014-3