The role of vascular lipids in Alzheimer's disease pathophysiology

项目摘要 脑血管是向大脑输送氧气和营养物质以及排出碳的关键。 二氧化碳和其他废物产品。虽然只占身体重量的2%，但20%的血液循环流向了 大脑，强调脑血管对大脑健康和功能的重要性。血样 中枢神经系统(CNS)的血管具有不同的物理、运输、代谢和 信号特性，称为血脑屏障(BBB)。表现在内皮细胞(ECs)内的那条线 作为中枢神经系统血管的管腔，这些血脑屏障特性严格地调节分子、离子、 以及血液和大脑之间的细胞，允许正常的神经元功能和保护神经 抗损伤和抗疾病的组织。因此，许多神经系统疾病都与血脑屏障紊乱有关， 包括多发性硬化症(MS)、癫痫和中风。 最近有研究表明，血脑屏障功能障碍可能与阿尔茨海默病的发病机制有关 疾病(AD)；然而，这种功能障碍的程度、性质和对AD病理生理学的贡献仍然存在 神秘莫测。识别AD患者脑血管的细微变化--血管特异性蛋白质组学方法 被雇佣了。这一方法揭示了与脂肪酸和脂肪有关的许多酶的下调。 AD患者皮质血管中ELOVL脂肪酸延伸酶7(ELOVL7)生物合成的比较 到控制程序。从这里开始，这项提议将检验这样一种假设，即异常的血管脂代谢是一个关键 AD病理生理学的组成部分。许多种类的脂类被牵连到管理贩运和 阿尔茨海默病相关酶的蛋白分解活性。由于脂质信号对大脑动态平衡、血管 完整性和AD病因学，识别AD期间血脑屏障中发生的脂体变化可以给出 对阿尔茨海默病发病机制的重要见解，并有可能确定可用于治疗的新靶点 目的：使AD患者血脑屏障正常化。 虽然ELOVL7从未在脑内皮细胞或AD的背景下进行过研究，但之前的研究已经 研究表明，ELOVL7在小鼠和人类的脑内皮细胞中都是独一无二的。此外，大脑EC特有 转录转录方法显示神经炎性小鼠ELOVL7表达动态丧失 已知血脑屏障中断的模型。这样的数据，再加上ELOVL7是 阿尔茨海默病患者脑血管系统的减少，使这一假设转向ELOVL7 可能是血脑屏障功能的关键，其下调可能与AD的病因有关。这一假说将 通过有条件地删除小鼠脑内皮细胞中的ELOVL7进行体内测试。理解ELOVL7的作用 At BBB可能阐明AD的重要病理生理学机制及其下游脂肪酸代谢产物 可能被证明是使AD的脑血管系统正常化的可行疗法。

Project Summary Cerebral blood vessels are critical to deliver oxygen and nutrients to the brain, and to remove carbon dioxide and other waste products. Although just 2% of the body’s weight, 20% of the circulation is directed to the brain, highlighting the importance of the cerebral vasculature to the health and function of the brain. Blood vessels that vascularize the central nervous system (CNS) harbor distinct physical, transport, metabolic, and signaling properties, termed the blood-brain barrier (BBB). Manifested within the endothelial cells (ECs) that line the lumen of the CNS vasculature, these BBB properties stringently regulate the movement of molecules, ions, and cells between the blood and the brain, allowing for proper neuronal function and safeguarding the neural tissue against injury and disease. As such, many neurological diseases are associated with BBB disruption, including multiple sclerosis (MS), epilepsy, and stroke. Recently it has been suggested that BBB dysfunction may contribute to the pathogenesis of Alzheimer’s disease (AD); however, the extent, nature, and contributions of this dysfunction to AD pathophysiology remains enigmatic. To identify nuanced changes to the brain vasculature in AD, a vascular-specific proteomic approach was employed. This approach revealed down-regulation of many enzymes involved in fatty acid and lipid biosynthesis, namely ELOVL fatty acid elongase 7 (ELOVL7), in the cortical vasculature of AD patients compared to controls. From here, this proposal will test the hypothesis that aberrant vascular lipid metabolism is a critical component of AD pathophysiology. Many classes of lipids have been implicated in regulating the trafficking and proteolytic activity of disease-relevant enzymes in AD. As lipid signaling is critical to brain homeostasis, vascular integrity, and AD etiology, identification of the lipidomic changes occurring at the BBB during AD could give important insight about the pathogenesis of AD and potentially identify novel therapeutic targets that can be used to normalize the BBB in AD patients. While ELOVL7 has never been studied in brain ECs or in the context of AD, previous studies have revealed that ELOVL7 is uniquely enriched in brain ECs in both mice and humans. Further, brain EC-specific transcriptomic approaches have shown dynamic loss of ELOVL7 expression in neuroinflammatory mouse models with known BBB disruption. Data such as these, taken together with the finding that ELOVL7 is decreased in the brain vasculature of patients with AD, steers this proposal towards the hypothesis that ELOVL7 may be critical to BBB function and that its downregulation may contribute to AD etiology. This hypothesis will be tested in vivo by conditional deletion of ELOVL7 within brain ECs of mice. Understanding the role of ELOVL7 at the BBB may elucidate crucial mechanisms of AD pathophysiology, and its downstream fatty acid metabolites may prove to be viable therapeutics to normalize the brain vasculature in AD.