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Apoptosis signal-regulating kinase 1 is a novel target molecule for cognitive impairment induced by chronic cerebral
Kensuke Toyama1, Nobutaka Koibuchi, Ken Uekawa
1From 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.).
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.
Insights
Apoptosis signal-regulating kinase 1 (ASK1) deficiency prevents cognitive decline caused by chronic cerebral hypoperfusion. Targeting the ASK1-p38 pathway may offer new treatments for vascular dementia and associated white matter lesions.
Area of Science:
- Neuroscience
- Molecular Biology
- Pathology
Background:
- Vascular dementia lacks specific treatments, with white matter lesions being a key pathology.
- Cerebral small vessel disease often leads to white matter lesions and cognitive impairment.
- The role of apoptosis signal-regulating kinase 1 (ASK1) in cerebral hypoperfusion-induced damage is not well understood.
Purpose of the Study:
- To investigate the role of ASK1 in the pathogenesis of cognitive impairment induced by chronic cerebral hypoperfusion.
- To determine if ASK1 is involved in blood-brain barrier disruption and white matter lesions.
- To explore ASK1 as a potential therapeutic target for vascular dementia.
Main Methods:
- A mouse model of chronic cerebral hypoperfusion was established using bilateral common carotid artery stenosis (BCAS).
- Cognitive function, white matter lesions, and blood-brain barrier integrity were assessed in wild-type and ASK1-deficient mice.
- Molecular markers of oxidative stress, inflammation, and endothelial tight junctions were analyzed.
Main Results:
- BCAS induced cognitive decline and white matter lesions in wild-type mice, but not in ASK1-deficient mice.
- ASK1 deficiency protected against BCAS-induced blood-brain barrier breakdown and endothelial tight junction disruption.
- Inhibition of ASK1 or p38 pathways ameliorated cognitive impairment in the mouse model.
Conclusions:
- The oxidative stress-ASK1-p38 signaling pathway contributes to cognitive impairment via blood-brain barrier disruption.
- ASK1 plays a critical role in the development of white matter lesions and cognitive decline following chronic cerebral hypoperfusion.
- ASK1 represents a promising therapeutic target for managing cognitive impairment associated with vascular dementia.
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