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

摘要：血管对认知损害和痴呆的贡献(VCID)是第二大致病原因 阿尔茨海默病(AD)是阿尔茨海默病(AD)的幕后推手，也是AD的常见共病。此外，有害的 血管病理与AD病理相结合的影响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 炎症增加会导致认知障碍。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 炎症通过TLR4途径激活，导致认知能力下降，从而加速痴呆/AD 病理学。目的1使用肝(肝细胞)和内皮特异性异或条件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，我们将使用全局和内皮特异的TLR4-/-小鼠，以及 通过生理学方法来操纵TLR4/NF-κB途径，同样是在慢性应激的背景下 并确定VCID的病理。在目标3中，我们将使用慢性应激和转换时异或活动的增加 通过补充亚硝酸盐将其不良氧化产物转化为一氧化氮，并测定其在病理上的作用 是VCID的。补充实验也将检查VCID和AD的相互作用，通过操纵 异或途径(使用febuxostat)和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该病的病因。 介导VCID的应激相关XOR和促炎变化及其向AD病理的进展。 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。

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.