title: Apoptosis signal-regulating kinase 1 is a novel target molecule for cognitive impairment induced by chronic cerebral hypoperfusion.
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.
  
  
  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.affiliation: 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.).
authors.forename: Kensuke
authors.initials: K
authors.lastname: Toyama
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Koibuchi
authors.forename: Ken
authors.initials: K
authors.lastname: Uekawa
authors.forename: Yu
authors.initials: Y
authors.lastname: Hasegawa
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Kataoka
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Katayama
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sueta
authors.forename: Ming Jie
authors.initials: MJ
authors.lastname: Ma
authors.forename: Takashi
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Osamu
authors.initials: O
authors.lastname: Yasuda
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Tomimoto
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
authors.forename: Hisao
authors.initials: H
authors.lastname: Ogawa
authors.forename: Shokei
authors.initials: S
authors.lastname: Kim-Mitsuyama
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D002545:Brain Ischemia / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control / Q000523:psychology; D016893:Carotid Stenosis / Q000150:complications* / Q000503:physiopathology / Q000523:psychology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003216:Conditioning, Operant / Q000502:physiology; D003337:Corpus Callosum / Q000098:blood supply; D015140:Dementia, Vascular / Q000201:enzymology / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control; D042783:Endothelial Cells / Q000201:enzymology; D005106:Exploratory Behavior; D048848:MAP Kinase Kinase Kinase 5 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008297:Male; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D009457:Neuroglia / Q000502:physiology; D018384:Oxidative Stress; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D021641:Recognition, Psychology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D019108:Tight Junctions; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse
keywords: ASK1 protein, mouse; blood–brain barrier; dementia, vascular