Abstract
Patients with vascular dementia, caused by cerebral ischemia, experience long-term cognitive impairment due to the lack of effective treatment. The mechanisms of and treatments for vascular dementia have been investigated in various animal models; however, the insufficient information on gene expression changes that define pathological conditions hampers progress. To investigate the underlying mechanism of and facilitate treatment development for vascular dementia, we established a mouse model of chronic cerebral hypoperfusion, including bilateral carotid artery stenosis, by using microcoils, and elucidated the molecular pathway underlying vascular dementia development. Rho-associated protein kinase (ROCK) 1/2, which regulates cellular structure, and inflammatory cytokines (IL-1 and IL-6) were upregulated in the vascular dementia model. However, expression of claudin-5, which maintains the blood–brain barrier, and MAP2 as a nerve cell-specific factor, was decreased in the hippocampal region of the vascular dementia model. Thus, we revealed that ROCK pathway activation loosens the tight junction of the blood–brain barrier and increases the influx of inflammatory cytokines into the hippocampal region, leading to neuronal death and causing cognitive and emotional dysfunction. Our vascular dementia model allows effective study of the vascular dementia mechanism. Moreover, the ROCK pathway may be a target for vascular dementia treatment development in the future.
Highlights
IntroductionVascular dementia is the second leading cause of dementia after Alzheimer’s disease (AD), and accounts for 30% of dementia cases in Asia
In order to implement an accurate disease model, we generated a bilateral carotid artery stenosis (BCAS) model and confirmed, by behavioral analysis, that it represented early vascular dementia. Using this model, we investigated the pathogenesis and underlying mechanisms of vascular dementia based on the putative pathways of hypoxia-induced inflammatory blood–brain barrier (BBB) disruption, Rho-associated protein kinase (ROCK)-induced cytoskeletal changes caused by vascular insufficiency, cell apoptosis, and structural changes in the cortex, corpus callosum, and hippo-campus
As a confirmed that spatial learning, short-term memory, spatial cognitive ability, and cognitive confirmation of early vascular dementia, we found that cell changes in CA1 levels in the ability were adversely affected by BCAS in the VD group [41,42,43,44]
Summary
Vascular dementia is the second leading cause of dementia after Alzheimer’s disease (AD), and accounts for 30% of dementia cases in Asia. 10,172 in acute stroke treatment), classifications of major stroke mechanisms, both in the US and Asia, exhibit a higher risk of ischemic stroke and vascular dementia [1,2,3]. Unlike dementia caused by AD, is accompanied by extracranial stenosis or intracranial stenosis and it arises from hemodynamic insufficiency in the brain. While cerebral hypoxic damage is considered the main pathogenic factor in vascular dementia, the mechanism of vascular dementia has not been elucidated in prior research [4,5,6]
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