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.

项目概要 阿尔茨海默病 (AD) 是一种进行性神经退行性疾病，影响 510 万老年人 65 岁或以上。慢性炎症是受 AD 影响的大脑中存在的病理学的核心特征。 对神经退行性变的炎症反应增加活性氧的产生和表达 细胞因子、粘附分子、补体蛋白和降解蛋白，细胞激活 小胶质细胞和星形胶质细胞，β 淀粉样蛋白的产生是淀粉样蛋白 B 所必需的。 在被诊断为正常认知的个体的脑脊液中的突触毒性。 APOE4基因型与脑脊液功能、轻度认知障碍和AD相关 补体 3、淀粉样蛋白 - β 和过度磷酸化 tau (ptau) C3 和 tau 之间的关联是。 仅在调整淀粉样蛋白后才显着。这些数据表明补体级联和 APOE4 存在显着差异。 导致 AD 神经变性升高，淀粉样蛋白调节补体级联反应对 来自遗传、临床和实验研究的新证据支持了下游 tau 蛋白病理学。 高密度脂蛋白 (HDL) 成分参与炎症、认知功能和进展 认知障碍 (CI) 与 HDL 蛋白 apoA-I、apoA-II 水平较低有关。 和 apoH 以及更高水平的 apoE 和 apoJ（簇蛋白） 超过 20 个与 HDL 代谢相关的位点。 有助于 AD 变异的风险，包括凝聚素。本研究旨在确定这种关联。 (1) 高密度脂蛋白 (HDL) 蛋白质组和 (2) 单核苷酸多态性 (SNP) 之间 在非裔美国人和白人成年人中，HDL 和炎症蛋白与 CI 和 AD 相关。 将根据地理地理原因中经过验证的 AD 病例的全基因组关联研究进行 和中风的种族差异（REGARDS）研究参与者。