Psychosocial Stress-Induced Vascular Contributions to Cognitive Impairment and Alzheimer's Disease: The Role of Xanthine Oxidase

心理社会压力诱发的血管对认知障碍和阿尔茨海默病的影响：黄嘌呤氧化酶的作用

• 批准号: 10206431
• 负责人: Paul D Chantler
• 金额: $ 51.81万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10206431
• 关键词: 3xTg-AD mouse; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid beta-Protein; Autopsy; Blood Circulation; Blood Vessels; Brain; Cerebrovascular Disorders; Chronic; Chronic stress; Clinical; Cognition; Cognitive; Data; Dementia; Dependovirus; Disease; Disease Progression; Drug Targeting; Effectiveness; Etiology; Event; Foundations; Future; Generations; Goals; Health; Hepatic; Hepatocyte; Hydrogen Peroxide; Impaired cognition; Inflammatory; Knock-out; Knockout Mice; Link; Liver; Mediating; Modeling; Molecular; Mus; Nitric Oxide; Nitrites; Outcome; Oxidants; Oxidative Stress; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Pharmacology; Physiological; Plasma; Process; Protocols documentation; Psychosocial Stress; Research; Research Design; Risk Factors; Role; Signal Pathway; Site; Source; Stress; Superoxides; TLR4 gene; Testing; Tissues; United States National Institutes of Health; Uric Acid; Vascular Cognitive Impairment; Vascular Dementia; Vascular Diseases; Work; XDH gene; Xanthine Oxidase; acid stress; brain tissue; cerebrovascular; clinical predictors; cognitive function; comorbidity; conditional knockout; defined contribution; drinking water; endothelial dysfunction; experimental study; febuxostat; improved; inhibitor/antagonist; loss of function; mouse toll-like receptor 4; negative affect; neuroinflammation; novel; overexpression; oxidant stress; prevent; response; synergism; tau Proteins; tool; vascular cognitive impairment and dementia

PROJECT SUMMARY / ABSTRACT Vascular contributions to cognitive impairment and dementia (VCID) is the second leading cause of dementia behind Alzheimer's disease (AD), and is a frequent co-morbidity with AD. Furthermore, the deleterious effect of vascular pathologies combined with AD pathology leads to increased likelihood of dementia. Despite the importance of VCID, little is known about its molecular mechanisms underlying vascular and cognitive dysfunction. This has led the NIH to prioritize studies examining vascular contributions to dementia, and its interplay with AD. Chronic psychosocial stress is a risk factor of VCID. Our preliminary data showing that chronic stress leads to considerable cerebrovascular and neuroinflammatory changes that have similar fundamental changes evident in the progression of AD has led us to focus on this process. Endothelial dysfunction is a critical determinant of vascular disease and predictor of clinical events. Xanthine oxidoreductase (XOR) is a major source of oxidative products (hydrogen peroxide and superoxide) and uric acid. The liver is the site of greatest XOR activity and the main source of circulating XOR activity. As such, XOR can negatively affect the vasculature. Our preliminary data suggest that chronic stress increases XOR activity resulting in cerebrovascular dysfunction and increased neuroinflammation leading to cognitive impairment. Our central hypothesis is that chronic stress elevates hepatic XOR, which is released into the circulation directly causing cerebrovascular dysfunction and the activation of neuroinflammation via a TLR4 pathway resulting in cognitive decline which accelerates dementia/AD pathology. Aim 1 uses a liver (hepatocyte)-specific XOR conditional KO (HXdh-/-) mouse and a liver-specific XOR overexpression tool to manipulate the XOR pathway during 8 weeks of chronic stress and to examine the pathology of VCID. In Aim 2, we will uses the TLR4-/- mouse, along with physiological and pharmacological approaches to manipulate the TLR4/NF-κB pathway, again in the context of chronic stress and determine VCID pathology. In Aim 3, we will use the increase in XOR activity with chronic stress and switch its bad oxidative products to nitric oxide by supplementing with nitrite and determine its actions on the pathology of VCID. Complementary experiments will also examine the interaction of VCID and AD, by manipulating the XOR pathway (using febuxostat or nitrite) and determining if we can delay the pathological progression of AD (3xTg- AD mice). Pilot data support this hypothesis. Thus, the overall goal of these studies is to determine the etiology of the stress-related XOR and pro-inflammatory changes in mediating VCID, and its progression to AD pathology. The studies will fill gaps identified by the NIH regarding the need for understanding of vascular contributions to cognitive impairment and dementia.

项目概要/摘要 血管对认知障碍和痴呆 (VCID) 的影响是痴呆的第二大原因 阿尔茨海默氏病 (AD) 是阿尔茨海默氏病 (AD) 的常见病，而且是 AD 的常见并发症。 尽管血管病变与 AD 病理相结合，但仍会导致痴呆的可能性增加。 VCID 的重要性，但对其血管和认知的分子机制知之甚少 这导致美国国立卫生研究院优先研究血管对痴呆及其疾病的影响。 慢性心理社会压力是 VCID 的一个危险因素。 压力会导致相当大的脑血管和神经炎症变化，这些变化具有相似的基本原理 AD 进展中的明显变化使我们关注这一过程的关键。 黄嘌呤氧化还原酶（XOR）是血管疾病的决定因素和临床事件的预测因子。 氧化产物（过氧化氢和超氧化物）和尿酸的来源肝脏是最大的部位。 XOR 活性和循环 XOR 活性的主要来源因此，XOR 会对脉管系统产生负面影响。 我们的初步数据表明，慢性压力会增加 XOR 活性，导致脑血管功能障碍 我们的中心假设是慢性压力会导致神经炎症增加。 升高肝脏XOR，释放到循环中直接导致脑血管功能障碍， 通过 TLR4 通路激活神经炎症，导致认知能力下降，从而加速 目标 1 使用肝脏（肝细胞）特异性 XOR 条件 KO (HXdh-/-) 小鼠和小鼠。 肝脏特异性 XOR 过表达工具，可在 8 周的慢性应激期间操纵 XOR 通路，并 检查 VCID 的病理学 在目标 2 中，我们将使用 TLR4-/- 小鼠以及生理学和病理学。 操纵 TLR4/NF-κB 通路的药理学方法，同样是在慢性应激和 确定 VCID 病理学 在目标 3 中，我们将利用 XOR 活性随慢性压力的增加并转换其值。 通过补充亚硝酸盐对一氧化氮产生不良氧化产物并确定其对病理学的作用 VCID 补充实验还将通过操纵 XOR 来检查 VCID 和 AD 的相互作用。 途径（使用非布索坦或亚硝酸盐）并确定我们是否可以延缓 AD 的病理进展 (3xTg- AD 小鼠）。因此，这些研究的总体目标是确定病因。 介导 VCID 中与应激相关的 XOR 和促炎性变化及其向 AD 病理学的进展。 这些研究将填补 NIH 确定的关于需要了解血管对 损伤和痴呆。