Metabolic Signatures Underlying Vascular Risk Factors for Alzheimer-type Dementias

 描述（由申请人提供）：代谢组学是一门全球性的生物化学科学，它为更详细地了解血管因素导致阿尔茨海默病复杂病因的生化机制提供了有利的工具。大量文献记录了脂质代谢改变与血管疾病（VD）以及淀粉样蛋白生成、神经传递、氧化应激和细胞凋亡之间的关系。特别是载脂蛋白E ε4（APOE ε4）等位基因，AD的主要危险因素，在脂质代谢/转运以及突触修复和淀粉样蛋白生成中具有重要的功能作用。这些先前的研究表明，脂质代谢和转运障碍是VD和AD发病机制的共同机制。然而，这一领域的研究主要集中在测量少量的血浆脂质，如胆固醇、甘油三酯和氧化磷脂，这些脂质主要由循环脂蛋白携带。这仅提供了脂质代谢的有限观点，并且不能提供对导致AD的心血管风险因素的详细机制见解。“脂质组学”是代谢组学的一个分支，是一门将生物化学与定量系统生物学和高通量技术结合在一起的新学科，为绘制疾病中的全球脂质变化（包括生化途径和代谢网络中的故障）提供了强有力的工具。四年多来，我们组建了一个跨学科的专家团队，包括代谢组学、脂质组学、遗传学、生物化学、生物信息学、神经心理学、生物标志物发现和临床试验，并开始定义AD轨迹中相互关联的生化途径中的扰动。我们自己的工作以及其他小组在AD研究中使用脂质组学和代谢组学方法的工作（Han，PLOS ONE 2011; Mapstone，Nature Medicine 2012）突出了早期疾病患者中磷脂酰胆碱（PC）、磷脂酰乙醇胺（PE）和乙醇胺缩醛磷脂（PlsEtn）以及鞘脂组（SL）的主要变化。其他人在心血管疾病（CVD）研究中的类似工作已经涉及CVD发病机制中这些相同脂质类别中的物种。这些脂质代谢的早期发现表明AD和CVD之间存在一些常见的代谢缺陷，并指出脂质组学有望提供有关VD对AD病理学贡献的更深入的机制见解。在本申请中，我们利用我们的跨学科专家团队以及我们与国家AD神经影像学倡议（ADNI）研究和基于社区的默多克记忆和认知健康研究（MHS）的合作伙伴关系来测试特定脂质类和网络的改变介导血管疾病和AD发病机制之间的联系的假设。我们将连接AD通路中的中枢和外周代谢缺陷，以测试有关影响疾病过程的全身血管和代谢因素的假设。

 DESCRIPTION (provided by applicant): Metabolomics, the global science of biochemistry, provides enabling tools for a more detailed understanding of the biochemical mechanisms by which vascular factors contribute to the complex etiology of Alzheimer's disease. An extensive literature documents a relationship between altered lipid metabolism and not only vascular disease (VD) but also amyloidogenesis, neurotransmission, oxidative stress, and apoptosis. In particular, the apolipoprotein E ε4 (APOE ε4) allele, a major risk factor for AD, has important functional roles in lipid metabolism/transport as well as synaptic repair and amyloidogenesis. These previous studies suggest that disturbances in lipid metabolism and transport are common mechanisms underlying both VD and AD pathogenesis. However, research in this area has focused primarily on measuring a small number of plasma lipids such as cholesterol, triglycerides, and oxidized phospholipids that are largely carried on circulating lipoproteins. Thi provides only a limited view of lipid metabolism and cannot provide detailed mechanistic insights into cardiovascular risk factors contributing to AD. "Lipidomics," a branch of metabolomics, is a new discipline that brings together biochemistry with quantitative systems biology and high-throughput techniques, providing powerful tools for mapping global lipid changes in disease including failures within biochemical pathways and metabolic networks. Over four years we have assembled an interdisciplinary team of experts in metabolomics, lipidomics, genetics, biochemistry, bioinformatics, neuropsychology, biomarker discovery and clinical trials, and have begun to define perturbations in interlinked biochemical pathways across the AD trajectory. Our own work as well as work by other groups using lipidomics and metabolomics approaches in the study of AD (Han, PLOS ONE 2011; Mapstone, Nature Medicine 2012) has highlighted major changes in phosphatidylcholines (PC), phophatidylethanolamines (PE) and ethanolamine plasmalogens (PlsEtn), and the sphingolipidome (SL) in patients with early disease. Similar work by others in the study of cardiovascular disease (CVD) has implicated species within these same lipid classes in CVD pathogenesis. These early findings with lipid metabolism suggest some common metabolic defects between AD and CVD and point to the promise of lipidomics in providing deeper mechanistic insights about a VD contribution to AD pathology. In this application we leverage our interdisciplinary team of experts and our partnerships with the national AD Neuroimaging Initiative (ADNI) study and the community-based MURDOCK Memory and Cognitive Health Study (MHS) to test hypotheses that alterations in specific lipid classes and networks mediate the links between vascular disease and AD pathogenesis. We will connect central and peripheral metabolic defects in AD pathways to test hypotheses about systemic vascular and metabolic factors affecting the disease process.