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

项目摘要/摘要 血管对认知损害和痴呆的贡献(VCID)是导致痴呆的第二大原因 阿尔茨海默病(AD)是阿尔茨海默病(AD)的幕后推手，常与AD并存。此外，毒气的有害影响 血管病理与AD病理相结合导致痴呆的可能性增加。尽管 VCID的重要性，对其在血管和认知方面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考虑研究血管对痴呆症的影响，以及它的 与AD互动。慢性心理社会压力是VCID的危险因素。我们的初步数据显示，慢性 应激导致大量脑血管和神经炎性改变，这些改变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素。黄嘌呤氧化还原酶(XOR)是一种重要的 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 XOR活性和循环XOR活性的主要来源。因此，异或会对血管系统产生负面影响。 我们的初步数据表明，慢性应激增加异或活动，导致脑血管功能障碍 并增加神经炎症，导致认知障碍。我们的中心假设是慢性压力 升高肝脏XOR，它直接释放到循环中，导致脑血管功能障碍和 通过TLR4通路激活神经炎症，导致认知功能减退，从而加速认知功能衰退 痴呆症/AD病理学。AIM 1使用肝脏(肝细胞)特异性异或条件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途径并 检查VCID的病理。在目标2中，我们将使用TLR4-/-小鼠，以及生理学和 再次在慢性应激和慢性应激的背景下，操纵TLR4/NF-κB途径的药理学方法 确定VCID病理。在目标3中，我们将使用慢性应激时异或活动的增加，并将其 补充亚硝酸盐将有害氧化产物转化为一氧化氮并测定其在心肌梗死病理中的作用 VCID。补充性实验还将通过操纵XOR来检验VCID和AD的交互作用 途径(使用非布索他汀或亚硝酸盐)，并确定我们是否可以延缓AD的病理进展(3xTg- 小白鼠)。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 与应激相关的异或和介导VCID的促炎变化，及其进展到AD病理。 这些研究将填补美国国立卫生研究院在了解血管对心脏的影响方面的空白。 认知障碍和痴呆症。

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.