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.

血管认知障碍和痴呆（VCID）是痴呆症最常见的病因 退伍军人。由于老年人口的比例正在逐渐增加，因此VCID已成为一个 对于老年人，尤其是退伍军人而言，重大问题。因此，该疾病的研究与 退伍军人的健康，因此是退伍军人管理局的使命。 VCID涉及多种危险因素，例如 作为高血压，心脏病，肥胖和2型糖尿病（T2DM）。超过4000万美国人 70岁或以上的年龄至少有这些代谢风险因素中的一个，但我们对如何了解 这些风险因素导致VCID。 最近，作为生物标志物和 血管疾病的危险因素。通过降低其分解代谢的表达/活性减少了ADMA分解代谢 在血管疾病的条件下，酶二甲基精氨酸二甲基氨基氢化酶（DDAH）。第二， DDAH功能障碍和ADMA高程导致内皮一氧化氮（NO）合酶的功能障碍 （eNOS）导致血管和内皮疾病。 adma uncouples eNOS导致氧化还原功能障碍 基于过量产生过氧亚硝酸盐（ONOOˉ），因此没有代谢。据报道，ADMA还会减少 脑血流（CBF）和血脑屏障（BBB）功能障碍。而CBF和BBB中断减少 已经高度与VCID的发病机理有关，ADMA在VCID相关的发病机理中的作用 目前尚不清楚潜在的内皮/血管机制。因此，目标的目标 拟议的研究是研究ADMA作为已知危险因素和 与VCID相关的脑病理学，并评估针对ADMA诱导的治疗策略 内皮eNOS/无针对VCID相关脑疾病的失调。 要了解VCID中ADMA介导的机制，我们最近研究了ADMA在 早期脑淀粉样血管病的小鼠模型中的血管和神经认知病理学（CAA：： TG-SWDI）。众所周知，CAA通过多种机制促进VCID，包括炎症， 灌注不足以及BBB功能和完整性的丧失。从这些初步调查中，我们发现 在CAA过程中，ADMA覆盖层导致BBB功能障碍增加，脑微血管的丧失， 神经炎症和认知能力下降，内皮硝化应激增加。这些发现导致我们 假设由于DDAH活动缺陷而导致血液或脑ADMA水平的覆盖率过高，驱动 通过干扰血管/内皮无体内稳态，大脑中与VCID相关的微血管发病机理。 VCID是一种多因素且复杂的疾病。因此，目前没有特定的动物模型是 被认为是评估VCID病理学和治疗的黄金标准。我们建议调查 使用CAA的两个小鼠模型和 与VCID发病机理最相关的慢性脑灌注（CCH）。 特定目的1：研究ADMA分解代谢受损在与VCID相关病理中的作用：研究 建议评估ADMA覆盖层和DDAH功能障碍作为疾病修饰因素和 因此，使用药品的VCID相关血管和神经认知病理学的治疗靶标 （外源ADMA治疗）和遗传（使用DDAH1-TG和DDAH1-KO小鼠）方法。 具体目的2：研究不平衡的无代谢（Onooˉ> gsno）在ADMA-的作用 诱导的脑微血管功能障碍：研究旨在研究机制 脑微血管及相关血管中eNOS活性的基础诱导的基本ADMA诱导的失调 疾病，特别是ADMA在没有新陈代谢的不平衡中的作用 （GSNO），在维持脑微血管内皮屏障完整性方面起着相反的作用。