Metabolic Signatures Underlying Vascular Risk Factors for Alzheimer-type Dementias

阿尔茨海默型痴呆症血管危险因素的代谢特征

• 批准号: 9005053
• 负责人: Rima F Kaddurah-Daouk
• 金额: $ 580.24万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9005053
• 关键词: Affect; Age; Alleles; Alzheimer' s Disease; Alzheimer' s Disease Pathway; Alzheimer' s disease risk; Amyloid; Apolipoprotein E; Apoptosis; Area; Authorization documentation; Biochemical; Biochemical Pathway; Biochemistry; Bioinformatics; Biological Markers; Blood; Blood Vessels; Brain; Cardiovascular Diseases; Cardiovascular system; Categories; Cholesterol; Cholesterol Homeostasis; Clinical; Clinical Data; Clinical Trials; Cognition; Cognitive; Communities; Complex; Data; Defect; Dependence; Discipline; Disease; Enrollment; Etiology; Event; Excision; Failure; Future; Genetic; Health; Hepatic; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Impaired cognition; Incidence; Individual; Intervention; Knowledge; Lecithin; Link; Lipids; Lipoproteins; Literature; Maps; Measures; Mediating; Medicine; Memory; Metabolic; Nature; Neuraxis; Neuropsychology; North Carolina; Oxidative Stress; Participant; Pathogenesis; Pathology; Pathway interactions; Patients; Peripheral; Phospholipids; Phosphorylcholine; Plasma; Process; Public Health; Reporting; Research; Risk; Risk Factors; Role; Sampling; Science; Serum; Shotguns; Sphingolipids; Sphingomyelins; Staging; Subgroup; Synapses; Systems Biology; Techniques; Testing; Triglycerides; Vascular Diseases; Work; amyloidogenesis; base; burden of illness; cardiovascular disorder risk; cardiovascular risk factor; cognitive function; cohort; community health study; disorder risk; ethanolamine plasmalogens; follow-up; functional disability; insight; lipid biosynthesis; lipid metabolism; lipid transport; member; metabolomics; neuroimaging; neurotransmission; novel; peripheral blood; phosphoethanolamine; pre-clinical; prevent; public health relevance; repaired; reverse cholesterol transport; synaptic function; tool; vascular factor

 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.

 描述（由申请人提供）：代谢组学是一门全球生物化学科学，为更详细地了解血管因素导致阿尔茨海默氏病复杂病因学的生化机制提供了有利的工具。大量文献记载了脂质代谢与阿尔茨海默氏病之间的关系。不仅涉及血管疾病 (VD)，还涉及淀粉样蛋白生成、神经传递、氧化应激和细胞凋亡，特别是载脂蛋白 E ε4 (APOE ε4)。等位基因是 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。然而，研究表明，脂质代谢和转运的紊乱是 VD 和 AD 发病机制的常见机制。该领域的研究主要集中于测量少量血浆脂质，例如胆固醇、甘油三酯和氧化磷脂，这些脂质主要由循环脂蛋白携带，只能提供有限的脂质代谢视图，不能提供详细的信息。 “脂质组学”是代谢组学的一个分支，它是一门新学科，它将生物化学与定量系统生物学和高通量技术结合起来，为绘制疾病中的全球脂质变化（包括内部失败）提供了强大的工具。四年来，我们组建了一支由代谢组学、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方面的跨学科专家团队。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开始定义 AD 轨迹中相互关联的生化途径的扰动（Han，PLOS ONE 2011；Mapstone，Nature Medicine 2012）强调了重大变化。磷脂酰胆碱 (PC)、磷脂酰乙醇胺 (PE) 和乙醇胺缩醛磷脂 (PlsEtn) 以及其他人在心血管疾病 (CVD) 研究中的类似工作表明，这些脂质类别中的物种与 CVD 发病机制有关。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为 VD 对 AD 病理学的贡献提供更深入的机制见解。在该应用中，我们利用我们的跨学科专家团队以及与国家 AD 神经影像计划 (ADNI) 研究和基于社区的 MURDOCK 记忆和认知健康研究 (MHS)，旨在检验特定脂质类别和网络的改变介导血管疾病与 AD 发病机制之间的联系的假设。我们将连接 AD 途径中的中枢和外周代谢缺陷，以检验有关全身血管的假设。以及影响疾病过程的代谢因素。