The role of vascular lipids in Alzheimer's disease pathophysiology

项目摘要 脑血管对于向大脑输送氧气和营养物质以及去除碳至关重要 二氧化碳和其他废物。虽然只有身体重量的2%，但20%的血液循环是直接进入心脏的。 大脑，强调脑血管系统对大脑健康和功能的重要性。血液 使中枢神经系统（CNS）血管化的血管具有不同的物理、运输、代谢和 信号传导特性，称为血脑屏障（BBB）。表现在内皮细胞（EC）中， 在CNS脉管系统的内腔中，这些BBB性质严格地调节分子，离子， 和细胞之间的血液和大脑，允许适当的神经功能和保护神经 防止受伤和疾病。因此，许多神经系统疾病与BBB破坏有关， 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有助于阿尔茨海默病的发病机制 然而，这种功能障碍对AD病理生理学的程度、性质和贡献仍然存在。 神秘莫测为了识别AD患者脑血管系统的细微变化， 被雇用了。这种方法揭示了参与脂肪酸和脂质代谢的许多酶的下调。 AD患者皮质血管系统中的脂肪酸生物合成，即脂肪酸延长酶7（ALVVL 7）， 控制。从这里，这项建议将测试的假设，异常血管脂质代谢是一个关键的 AD病理生理学的组成部分。许多种类的脂质都涉及到调节贩运和 AD中疾病相关酶的蛋白水解活性。由于脂质信号传导对脑内稳态至关重要， 完整性和AD病因，AD期间BBB发生的脂质组学变化的鉴定可以提供 关于AD发病机制的重要见解，并可能确定可用于治疗的新靶点 使AD患者的BBB正常化。 虽然从未在脑EC或AD背景下研究过BLV7，但先前的研究已经证实了BLV7的存在。 结果显示，在小鼠和人的脑EC中都独特地富集了HPVL7。此外，脑EC特异性 转录组学方法显示神经炎症小鼠中ELOVL7表达的动态丧失 已知BBB破坏的模型。诸如此类的数据，连同发现， AD患者的脑血管系统中的VEGF7减少，将该提议转向了以下假设： 可能对BBB功能至关重要，其下调可能有助于AD病因学。这一假设将 通过在小鼠脑EC内有条件地缺失CD3VL7来体内测试。了解ESPVL7的作用 可能阐明AD病理生理学及其下游脂肪酸代谢产物的重要机制 可能被证明是使AD中的脑血管正常化的可行疗法。

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.