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: 10669630
• 负责人: Paul D Chantler
• 金额: $ 50.08万
• 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/10669630
• 关键词: 3xTg-AD mouse; Acceleration; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Amyloid beta-Protein; Autopsy; Blood; Blood Vessels; Brain; Cerebrovascular Disorders; Chronic; Chronic stress; Circulation; 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; Physiological; Plasma; Process; Protocols documentation; Psychosocial Stress; Receptor Signaling; Research; Research Design; Risk Factors; Role; Signal Pathway; Site; Source; Stress; Superoxides; 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; pharmacologic; prevent; receptor; 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.

翻译后摘要：血管的贡献，认知障碍和痴呆症（VCID）是第二大原因， 阿尔茨海默病（AD）是阿尔茨海默病（Alzheimer's disease，AD）之后的痴呆，并且是AD的常见共病。此外，有害的 与AD病理学结合的血管病理学的影响导致痴呆的可能性增加。尽管 尽管VCID的重要性，但其在血管和认知功能方面的分子机制却知之甚少 功能障碍这使得NIH优先研究血管对痴呆的贡献， 与AD相互作用慢性心理社会应激是VCID的危险因素。我们的初步数据显示， 应激导致相当大的脑血管和神经炎性变化，这些变化具有类似的基础 AD进展中的明显变化使我们关注这一过程。内皮功能障碍是一个关键的 血管疾病的决定因素和临床事件的预测因素。黄嘌呤氧化还原酶（XOR）是一种主要的 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 异或运算和循环异或运算的主要来源。因此，XOR可能对脉管系统产生负面影响。 我们的初步数据表明，慢性应激增加XOR活动，导致脑血管功能障碍 炎症增加导致认知障碍我们的核心假设是慢性压力 升高肝脏XOR，其释放到循环中直接引起脑血管功能障碍， 通过TLR 4途径激活炎症，导致认知能力下降，从而加速痴呆/AD 病理目的1使用肝脏（肝细胞）和内皮特异性XOR条件性KO（HXdh-/-）小鼠和 肝脏特异性XOR过表达工具在8周慢性应激期间操纵XOR通路， 检查VCID的病理。在目标2中，我们将使用全局和内皮特异性TLR 4-/-小鼠，沿着 再次在慢性应激的背景下，用生理学方法操纵TLR 4/NF-κB通路， 并确定VCID病理学。在目标3中，我们将使用慢性应激和转换时XOR活性的增加， 通过补充亚硝酸盐，观察其对一氧化氮的不良氧化产物，并测定其对病理的作用 的VCID。补充实验也将检查VCID和AD的相互作用，通过操纵 XOR途径（使用非布司他）并确定我们是否可以延迟AD的病理进展（3xTg-AD 小鼠）。试点数据支持这一假设。因此，这些研究的总体目标是确定 应激相关的XOR和促炎性改变介导VCID，以及其向AD病理学的进展。 这些研究将填补美国国立卫生研究院确定的关于需要了解血管对 认知障碍和痴呆。

项目成果

Left Ventricular Segmental Strain Identifies Unique Myocardial Deformation Patterns After Intrinsic and Extrinsic Stressors in Mice.

• DOI: 10.1016/j.ultrasmedbio.2022.06.004
• 发表时间: 2022-10
• 期刊: ULTRASOUND IN MEDICINE AND BIOLOGY
• 影响因子: 2.9
• 作者: Kunovac, A. M. I. N. A.;Hathaway, Quincy A.;Burrage, Emily N.;Coblentz, T. Y. L. E. R.;Kelley, Eric E.;Sengupta, Partho P.;Hollander, John M.;Chantler, Paul D.
• 通讯作者: Chantler, Paul D.