Kensuke Toyama1, Nobutaka Koibuchi, Ken Uekawa, Yu Hasegawa, Keiichiro Kataoka, Tetsuji Katayama, Daisuke Sueta, Ming Jie Ma, Takashi Nakagawa, Osamu Yasuda, Hidekazu Tomimoto, Hidenori Ichijo, Hisao Ogawa, Shokei Kim-Mitsuyama. 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.
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.
Authors: Kristen L Zuloaga; Wenri Zhang; Lauren A Yeiser; Blair Stewart; Ayaka Kukino; Xiao Nie; Natalie E Roese; Marjorie R Grafe; Martin M Pike; Jacob Raber; Nabil J Alkayed Journal: Transl Stroke Res Date: 2015-06-05 Impact factor: 6.829
Authors: Arati Patel; Alimohammad Moalem; Hank Cheng; Robin M Babadjouni; Kaleena Patel; Drew M Hodis; Deep Chandegara; Steven Cen; Shuhan He; Qinghai Liu; William J Mack Journal: Neurol Res Date: 2017-08-22 Impact factor: 2.448
Authors: Kristen L Zuloaga; Lance A Johnson; Natalie E Roese; Tessa Marzulla; Wenri Zhang; Xiao Nie; Farah N Alkayed; Christine Hong; Marjorie R Grafe; Martin M Pike; Jacob Raber; Nabil J Alkayed Journal: J Cereb Blood Flow Metab Date: 2015-11-11 Impact factor: 6.200