Mechanism of Vascular Impairment in Neurocognitive Disorders

神经认知障碍中血管损伤的机制

• 批准号: 10343797
• 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/10343797
• 关键词: Age; Alzheimer' s Disease; American; Amyloid; Animal Model; Attention; Biological Markers; Blood; Blood - brain barrier anatomy; Blood Vessels; 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; Gold; Health; Heart Diseases; Hemorrhage; Homeostasis; Human; Hypertension; Impaired cognition; Impairment; Inflammation; Investigation; Ischemia; Knockout Mice; Laboratories; Maintenance; Mediating; Metabolic; Metabolic syndrome; Metabolism; Microvascular Dysfunction; Mission; Mus; N,N-dimethylarginine; NOS3 gene; Neurocognitive; Neurons; Nitric Oxide; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oxidation-Reduction; Pathogenesis; Pathologic; Pathology; Patients; Peroxonitrite; Pharmacology; Play; Population; Production; Proteins; Regulation; Reporting; Research; Risk; 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; base; 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; 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.

血管性认知功能障碍和痴呆（VCID）是老年痴呆最常见的病因 包括退伍军人由于老年人口的比例逐渐增加，VCID已成为一个 这对老年人，尤其是退伍军人来说是个大问题。因此，对这种疾病的研究与 退伍军人的健康，因此退伍军人管理局的使命。VCID涉及多种风险因素，例如 如高血压、心脏病、肥胖和2型糖尿病（T2 DM）。超过四千万美国人 70岁或以上的老年人至少有一种代谢危险因素，但我们对如何做到这一点知之甚少。 这些危险因素导致VCID。 最近，血液中不对称二甲基精氨酸（ADMA）的升高作为生物标志物而受到关注， 血管疾病的危险因素。ADMA催化剂通过其分解代谢酶的表达/活性降低而减少。 酶二甲基精氨酸二甲基氨基水解酶（DDAH）在血管疾病的条件下。第二、 DDAH功能障碍和ADMA升高导致内皮型一氧化氮合酶功能障碍 （eNOS）导致血管和内皮疾病。ADMA解偶联eNOS导致氧化还原功能障碍- 以NO代谢为基础，过量产生过氧亚硝酸盐（ONOO）。据报道，ADMA还可以减少 脑血流量（CBF）和血脑屏障（BBB）功能障碍。降低脑血流量和血脑屏障破坏 与VCID的发病机制密切相关，ADMA在VCID相关发病机制中的作用， 目前对潜在的内皮/血管机制还没有很好的了解。因此，目标 拟议的研究是调查ADMA作为已知风险因素和 研究中，我们还评估了靶向ADMA诱导的VCID相关脑病理的治疗策略。 内皮eNOS/NO失调与VCID相关的脑疾病 为了了解ADMA介导的VCID机制，我们最近研究了ADMA在VCID中的作用。 在早发性脑淀粉样血管病（CAA： Tg-SwDI）。已知CAA通过多种机制促进VCID，包括炎症， 灌注不足和BBB功能和完整性丧失。从这些初步调查中，我们发现， CAA过程中ADMA超负荷导致BBB功能障碍增加，脑微血管损失， 神经炎症和认知能力下降伴内皮亚硝化应激增加。这些发现让我们 假设由于DDAH活性缺陷导致血液或大脑ADMA水平过高， 通过干扰血管/内皮NO稳态的脑中的VCID相关微血管发病机制。 VCID是一种多因素和复杂的疾病。因此，目前还没有特定的动物模型， 被认为是评估VCID病理和治疗的金标准。我们建议调查 ADMA在VICD发病机制和潜在机制中的作用，使用两种CAA小鼠模型， 慢性脑灌注不足（CCH），这是最相关的VCID发病机制。 具体目的1：研究受损的ADMA催化剂在VHD相关病理学中的作用：研究 建议评估ADMA过载和DDAH功能障碍作为疾病修饰因子的作用， 因此，使用药理学方法治疗VHD相关的血管和神经认知病理学的治疗靶点 （外源性ADMA处理）和遗传（使用DDAH 1-Tg和DDAH 1-Ko小鼠）方法。 具体目的2：研究NO代谢失衡（ONOO β> GSNO）在ADMA中的作用。 诱导的微血管功能障碍：研究旨在研究其机制 潜在的ADMA诱导的脑微血管和相关血管中eNOS活性失调 疾病，特别是ADMA在NO代谢不平衡中的作用，ONOO谷胱甘肽与S-亚硝基谷胱甘肽 （GSNO），其在维持脑微血管内皮屏障完整性中发挥相反的作用。