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: 10470769
• 负责人: Paul D Chantler
• 金额: $ 50.76万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10470769
• 关键词: 3xTg-AD mouse; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Amyloid beta-Protein; Autopsy; Blood; Blood Circulation; Blood Vessels; Brain; Cerebrovascular Disorders; Chronic; Chronic stress; Clinical; Cognition; Cognitive; Data; Dementia; Dependovirus; Development; Disease; Drug Targeting; Endothelium; Etiology; Event; Foundations; Functional disorder; Future; Generations; Goals; Health; Hepatic; Hepatocyte; Hydrogen Peroxide; Impaired cognition; Impairment; Inflammation; Inflammatory; Knock-out; Knockout Mice; Link; Liver; Mediating; Modeling; Molecular; Mus; Nitric Oxide; Nitrites; Nitrogen Dioxide; 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; cerebrovascular pathology; clinical predictors; cognitive function; comorbidity; conditional knockout; drinking water; endothelial dysfunction; experimental study; febuxostat; improved; inhibitor; mouse toll-like receptor 4; negative affect; neuroinflammation; novel; overexpression; oxidoreductase inhibitor; prevent; receptor expression; synergism; tau Proteins; tool; vascular cognitive impairment and dementia; vascular contributions; vascular inflammation

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 inflammation 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 inflammation via a TLR4 pathway resulting in cognitive decline which accelerates dementia/AD pathology. Aim 1 uses a liver (hepatocyte)-and endothelial-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 use the global-and- endothelial-specific TLR4-/- mouse, along with physiological 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) 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.

摘要：血管导致认知障碍和痴呆（VCID）是导致认知障碍和痴呆的第二大原因。 痴呆症是阿尔茨海默病 (AD) 的幕后黑手，也是 AD 的常见并发症。此外，有害的 血管病理学与 AD 病理学相结合的影响导致痴呆的可能性增加。尽管 VCID 的重要性，但对其血管和认知的分子机制知之甚少 功能障碍。这导致美国国立卫生研究院优先研究血管对痴呆症的影响及其影响 与AD相互作用。慢性社会心理压力是 VCID 的危险因素。我们的初步数据显示，慢性 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 进展过程中的明显变化促使我们关注这一过程。内皮功能障碍是一个关键 血管疾病的决定因素和临床事件的预测因子。黄嘌呤氧化还原酶（XOR）是一种主要的酶 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活动和循环XOR活动的主要来源。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 炎症增加导致认知障碍。我们的中心假设是，慢性压力 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 通路激活炎症，导致认知能力下降，从而加速痴呆/AD 病理。目标 1 使用肝脏（肝细胞）和内皮细胞特异性 XOR 条件 KO (HXdh-/-) 小鼠和 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，我们将使用全局和内皮特异性 TLR4-/- 小鼠，以及 同样是在慢性压力的背景下，用生理学方法来操纵 TLR4/NF-κB 通路 并确定 VCID 病理。在目标 3 中，我们将利用 XOR 活动随着慢性压力和开关的增加 补充亚硝酸盐对一氧化氮的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 VCID 和 AD 的相互作用来检查 XOR 途径（使用非布索坦）并确定我们是否可以延缓 AD 的病理进展 (3xTg-AD 老鼠）。试点数据支持这一假设。因此，这些研究的总体目标是确定病因 应激相关的 XOR 和促炎性变化介导 VCID 及其进展为 AD 病理学。 这些研究将填补 NIH 确定的关于需要了解血管对 认知障碍和痴呆。