Use of High Density Lipoprotein Proteome in the Prediction of Cognitive Impairment and Alzheimer's Disease: (REGARDS)

使用高密度脂蛋白蛋白质组预测认知障碍和阿尔茨海默病：（问候）

• 批准号: 10091375
• 负责人: Robert Sidney Rosenson
• 金额: $ 53.21万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10091375
• 关键词: Abeta synthesis; Activities of Daily Living; Adult; Affect; African American; Age; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease risk; American; Amyloid; Amyloid beta-Protein; Apolipoprotein A-I; Apolipoprotein A-II; Apolipoprotein E; Appointment; Astrocytes; Biological Assay; Brain; Case-Control Studies; Cell Adhesion Molecules; Cerebrospinal Fluid; Cholesterol; Chronic; Clinical Research; Cognitive; Collection; Complement; Complement 1q; Complement 3; Data; Dementia; Diagnosis; Education; Follow-Up Studies; Genes; Genetic study; Genotype; Goals; High Density Lipoproteins; Impaired cognition; Impairment; Individual; Inflammation; Inflammatory; Inflammatory Response; Ions; Isotopes; Laboratories; Link; Lipids; Mass Spectrum Analysis; Measures; Mediating; Medicare; Memory; Metabolism; Methods; Microglia; Monitor; National Institute on Aging; Nerve Degeneration; Neurodegenerative Disorders; Participant; Pathogenesis; Pathology; Pharmaceutical Preparations; Phenotype; Physicians; Physiological; Play; Production; Property; Proteins; Proteome; Proteomics; Race; Reaction; Reactive Oxygen Species; Reasons for Geographic And Racial Differences in Stroke; Reporting; Research; Role; Sampling; Semantics; Shotguns; Single Nucleotide Polymorphism; Stroke; Testing; Variant; Vascular Cognitive Impairment; aged; base; cognitive development; cognitive function; cytokine; design; experimental study; financial decision making; functional decline; functional disability; genome wide association study; hyperphosphorylated tau; immunoregulation; informant; mild cognitive impairment; mouse model; nanoparticle; neuroinflammation; particle; protein distribution; role model; sex; sulfated glycoprotein 2; tau Proteins

PROJECT SUMMARY Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that afflicts 5.1 million Americans aged 65 or older. Chronic inflammation is a central feature of the pathology present in AD-affected brains. Inflammatory responses to neurodegeneration increase production of reactive oxygen species, and expression of cytokines, adhesion molecules, complement proteins, and degradative proteins, cellular activation of microglia and astrocytes, and production of beta amyloid. Complement C1q is necessary for amyloid-B synaptoxicity in murine models. In the cerebrospinal fluid of individuals diagnosed with normal cognitive function, mild cognitive impairment and AD, APOE4 genotype was associated with cerebrospinal fluid complement 3, amyloid – beta and hyperphosphorylated tau (ptau). The association between C3 and tau was significant only after adjustment for amyloid. These data suggest that the complement cascade and APOE4 results in elevated AD neurodegeneration and that amyloid regulates the effect of the complement cascade on downstream tau pathology. Emerging evidence from genetic, clinical and experimental studies support the involvement of high-density lipoprotein (HDL) constituents in inflammation, cognitive function and progression to AD. Cognitive impairment (CI) has been associated with lower levels of the HDL proteins apoA-I, apoA-II and apoH and higher levels of apoE and apoJ (clusterin). More than 20 loci associated with HDL metabolism contribute to the risk of AD including variants in clusterin. This study is designed to determine the association between (1) the high-density lipoprotein (HDL) proteome and (2) single nucleotide polymorphisms (SNPs) related with HDL and inflammatory proteins with CI and AD in African-American and white adults. This study will be conducted from a genome wide association study of validated cases of AD in REasons for Geographic and Racial Differences in Stroke (REGARDS) study participants.

项目总结 阿尔茨海默病(AD)是一种进行性神经退行性疾病，困扰着510万美国老年人 65岁或以上。慢性炎症是阿尔茨海默病患者大脑病理的中心特征。 神经退行性变的炎症反应增加了活性氧的产生和表达 在细胞因子、黏附分子、补体蛋白和降解蛋白中，细胞激活 小胶质细胞和星形胶质细胞，以及β淀粉样蛋白的产生。补体C1q是淀粉样蛋白B所必需的 小鼠模型中的突触毒性。在被诊断为认知正常的人的脑脊液中 功能、轻度认知损害和AD、APOE4基因与脑脊液相关 补体3、淀粉样β蛋白和过度磷酸化的tau(Ptau)。C3和tau之间的联系是 仅在对淀粉样蛋白进行调整后才显着。这些数据表明，补体级联和APOE4 结果阿尔茨海默病神经变性加剧，淀粉样蛋白调节补体级联作用 下游的tau病理。来自遗传学、临床和实验研究的新证据支持 高密度脂蛋白成分与炎症、认知功能和进展的关系 到公元后。认知障碍(CI)与低水平的高密度脂蛋白apoA-I、apoA-II有关 和apoH，以及较高水平的apoE和apoJ(Clusterin)。20多个与高密度脂蛋白代谢相关的基因座 增加AD的风险，包括聚集素的变异体。这项研究旨在确定两者之间的联系 在(1)高密度脂蛋白蛋白质组和(2)单核苷酸多态(SNPs)之间 非裔美国人和白人成人脑梗塞和阿尔茨海默病与高密度脂蛋白和炎症蛋白的关系。本研究 将从《地理原因》中对确诊AD病例的全基因组关联研究中进行 和中风的种族差异(涉及)研究参与者。