Apoptosis Signal–Regulating Kinase 1 Is a Novel Target Molecule for Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion
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.
- Received March 28, 2013.
- Accepted December 16, 2013.
- © 2013 American Heart Association, Inc.