Mechanism of Vascular Impairment in Neurocognitive Disorders

神经认知障碍中血管损伤的机制

• 批准号: 10553093
• 负责人: Avtar K Singh
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10553093
• 关键词: Age; Alzheimer' s Disease; Alzheimer' s disease patient; American; Amyloid; Animal Model; Attention; Biological Markers; Blood; Blood - brain barrier anatomy; Blood Vessels; Blood brain barrier dysfunction; Brain; Brain Diseases; Brain Pathology; Catabolism; Cell Culture Techniques; Cerebral Amyloid Angiopathy; Cerebrovascular Circulation; Cerebrum; Chronic; Cognition; Complex; Dementia; Disease; Drug Targeting; Elderly; Endothelial Cells; Endothelium; Enzymes; Etiology; Expectancy; F-Actin; Functional disorder; Genetic; Goals; Health; Heart Diseases; Hemorrhage; Homeostasis; Human; Hypertension; Impaired cognition; Impairment; Inflammation; Investigation; Ischemia; Knockout Mice; Laboratories; Maintenance; Mediating; Metabolic; Metabolic syndrome; Metabolism; Mission; Mutant Strains Mice; N,N-dimethylarginine; NOS3 gene; Neurocognitive; Neurons; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oxidation-Reduction; Pathogenesis; Pathologic; Pathology; Peroxonitrite; Play; Population; Production; Proteins; Regulation; Reporting; Research; Risk Factors; Role; S-Nitrosoglutathione; Stress Fibers; Study models; Syndrome; Therapeutic; Transgenic Mice; United States Department of Veterans Affairs; Validation; Vascular Diseases; Vascular Endothelium; Veterans; abeta deposition; age related; aged; blood-brain barrier disruption; blood-brain barrier function; cerebral hypoperfusion; cerebral microvasculature; design; dimethylargininase; early onset; endothelial dysfunction; hemodynamics; hypoperfusion; inhibitor; insight; mouse model; mutant; neurocognitive disorder; neuroinflammation; neurovascular; nitrosative stress; pharmacologic; therapeutic target; vascular cognitive impairment and dementia; wasting

Vascular cognitive impairment and dementia (VCID) is the most common etiology of dementia in the elderly including veterans. Since proportion of the elderly population is progressively increasing, VCID has become a significant problem for elderly citizens, especially veterans. Therefore, the study of this disease is relevant to veterans’ health and thus the mission of the Veterans Administration. VCID involves multiple risk factors, such as hypertension, cardiac disease, obesity, and type 2 diabetes mellitus (T2DM). Over 40 million Americans aged 70 years or older have at least one of these metabolic risk factors, yet we know relatively little about how these risk factors contribute to VCID. Recently, elevation of asymmetric dimethylarginine (ADMA) in blood has gained attention as a biomarker and a risk factor for vascular disease. ADMA catabolism is reduced by decreased expression/activity of its catabolic enzyme dimethylarginine dimethylaminohydrolase (DDAH) under conditions of vascular disease. Secondly, DDAH dysfunction and ADMA elevation contribute to dysfunction of endothelial nitric oxide (NO) synthase (eNOS) leading to vascular and endothelial disease. ADMA uncouples eNOS leading to dysfunction of redox- based NO metabolism with excessive production of peroxynitrite (ONOOˉ). ADMA is also reported to reduce cerebral blood flow (CBF) and blood-brain barrier (BBB) dysfunction. While decreased CBF and BBB disruption have been highly implicated in the pathogenesis of VCID, the role of ADMA in VCID-related pathogenesis, as well as underlying endothelial/vascular mechanisms are not well understood at present. Therefore, the goal of proposed study is to investigate ADMA as an intermediary mechanism between the known risk factors and VCID-related brain pathologies and to evaluate the therapeutic strategies targeting the ADMA-induced endothelial eNOS/NO dysregulation for VCID associated brain disease. To understand ADMA-mediated mechanisms in VCID, we have recently investigated the role of ADMA in vascular and neurocognitive-pathologies in a mouse model of early-onset cerebral amyloid angiopathy (CAA: Tg-SwDI). CAA is known to promote VCID through a number of mechanisms including inflammation, hypoperfusion, and loss of BBB function and integrity. From these initial investigations, we discovered that ADMA overburden during the course of CAA causes an increased BBB dysfunction, loss of brain microvessels, neuroinflammation, and cognitive decline with increased endothelial nitrosative stress. These findings led us to hypothesize that overburden of blood or brain ADMA levels, as a result of defective DDAH activity, drives VCID-related microvascular pathogenesis in the brain by disturbing the vascular/endothelial NO homeostasis. VCID is a multifactorial and complex disease. At present, therefore, there is no specific animal model that is considered as the gold standard for assessing VCID pathology and therapeutics. We propose to investigate the role of ADMA in VICD pathogenesis and underlying mechanisms using two mouse models of CAA and chronic cerebral hypoperfusion (CCH) which are the most relevant to VCID pathogenesis. Specific Aim 1: To investigate the role of impaired ADMA catabolism in VCID-related pathologies: Studies are proposed to assess the role of ADMA overburden and DDAH dysfunction as disease modifying factors and thus therapeutic targets for VCID-associated vascular and neurocognitive pathologies using the pharmacological (exogenous ADMA treatment) and genetic (use of DDAH1-Tg and DDAH1-Ko mice) approaches. Specific Aim 2: To investigate the role of imbalanced NO metabolism (ONOOˉ > GSNO) in ADMA- induced cerebro-microvascular dysfunction: Studies are designed to investigate the mechanism(s) underlying ADMA-induced dysregulation of eNOS activity in brain microvessels and associated vascular disease, specifically, the role of ADMA in imbalance of NO metabolism to ONOOˉ vs. S-nitrosoglutathione (GSNO), which play opposing roles in maintenance of brain microvessel endothelial barrier integrity.

血管性认知障碍和痴呆（VCID）是老年痴呆最常见的病因