Journal
BIOMEDICINES
Volume 10, Issue 2, Pages -Publisher
MDPI
DOI: 10.3390/biomedicines10020446
Keywords
animal model; behavior test; biomarker; blood-brain barrier; cognitive dysfunction; inflammation; memory dysfunction; neuronal cell death; Rho-associated protein kinase; vascular dementia
Categories
Funding
- Jeollanam-do Science and Technology R&D Project (Development of stem cell-derived new drug) - Jeollanam-do, Korea
- Soonchunhyang University Fund
- Bio & Medical Technology Development Program of the National Research Foundation - Korean government [NRF2019M3E5D1A02069061, NRF-2020R1F1A1066362]
- Korea Medical Device Development Fund - Korea government (the Ministry of Science and ICT) [202015 x 17]
- Korea Medical Device Development Fund - Korea government (Ministry of Trade, Industry and Energy) [202015 x 17]
- Korea Medical Device Development Fund - Korea government (Ministry of Health & Welfare, Republic of Kore) [202015 x 17]
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Patients with vascular dementia caused by cerebral ischemia lack effective treatment, and insufficient information on gene expression changes hampers progress. By establishing a mouse model, we revealed that activation of the ROCK pathway increases the influx of inflammatory cytokines into the hippocampal region, leading to neuronal death and cognitive and emotional dysfunction.
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.
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