Comprehensive Characterization of Glycosylation Alterations in Alzheimer’s Disease

阿尔茨海默病糖基化改变的综合表征

• 批准号: 9789176
• 负责人: LEE-WAY JIN
• 金额: $ 66.4万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789176
• 关键词: Address; Advanced Development; Affect; Aging; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease risk; Alzheimer’s disease biomarker; American; Amyloid beta-Protein; Apolipoprotein E; Apoproteins; Area; Biological Markers; Biological Process; Blood; Brain; Brain Diseases; Brain region; California; Cell Surface Receptors; Cerebrospinal Fluid; Cholesterol; Clinical; Complex; Critical Pathways; Data; Defect; Dementia; Development; Diagnostic; Disease; E protein; Early Diagnosis; Enzymes; Excision; Funding; Gene Expression; Genotype; Glycobiology; Glycolipids; Glycoproteins; Healthcare; High Density Lipoproteins; Human; Impaired cognition; Inflammation; Inflammatory Response; Intervention; Investments; Link; Lipids; Lipoproteins; Low-Density Lipoproteins; Maps; Mass Spectrum Analysis; Measures; Mediating; Metabolism; Methods; Microglia; Mission; Monitor; Neurodegenerative Disorders; Pathology; Patients; Pattern; Peripheral; Plasma; Play; Polysaccharides; Prevalence; Prevention; Prevention strategy; Preventive treatment; Protein Glycosylation; Protein Isoforms; Proteins; Quality of life; Reproducibility; Research; Role; Sampling; Screening procedure; Site; Specificity; Structural Protein; Structure; TREM2 gene; Therapeutic; Time; Tissues; Universities; Very low density lipoprotein; analytical method; analytical tool; apolipoprotein D; apolipoprotein E-3; apolipoprotein E-4; base; biomarker development; biomarker discovery; brain tissue; cognitive function; cost; cytokine; differential expression; early detection biomarkers; genetic risk factor; glycosylation; glycosyltransferase; immunoreactivity; improved; intercellular communication; liquid chromatography mass spectrometry; macrophage; mind control; minimally invasive; mouse model; neuroinflammation; non-demented; novel; novel therapeutics; precision medicine; prevent; protein structure; protein structure function; public health priorities; receptor; research and development; screening; sugar; tool

Project Summary Alzheimer’s disease (AD) is a debilitating neurodegenerative disease that is growing in prevalence despite decades of investment in the research and development of diagnostics and therapeutics. Because of the high healthcare burden and devastating effects of AD on cognitive function and quality of life, early biomarkers of disease and interventions to prevent and treat AD are a public health priority. The search for biomarkers and treatments has turned to glycobiology, the study of complex sugars attached to proteins and lipids. The post- translational glycosylation of proteins and lipids plays a role in a number of critical biological processes including cell-to-cell communication and signaling, and protein structure and function. Recently, major alterations in glycosylation have been documented in the brains, cerebrospinal fluid, and blood of AD patients even before the onset of advanced cognitive decline. Glycosylation is likely to be causally involved in AD, thus measuring glycosylation in blood is a promising strategy for discovering early biomarkers. Apolipoprotein E (ApoE) is the single greatest genetic risk factor for AD. Carriers of the ApoE4 isoform are 4-12 times more likely to develop AD depending on the number of copies of ApoE4, and develop the disease as many as 20 years earlier. ApoE is a glycosylated protein, and nearly all of the proteins, carriers, and receptors involved in its metabolism are also glycosylated. The structure of ApoE heavily influences its functionality. Glycosylation is known to alter protein structure yet neither the glycosylation of ApoE, nor the overall glycosylation in the brain and in the blood have been adequately characterized in Alzheimer’s disease patients because the lack of precise analytical tools for measuring glycosylation has been a technological barrier to progress. Our group has pioneered the development of advanced and sensitive liquid chromatography-mass spectrometry methods as tools to precisely measure glycosylation alterations across hundreds of lipids and proteins simultaneously. Our method is rapid-throughput and can monitor the site-specificity, structure specificity, and linkage specificity of all attached glycans in hundreds of clinical samples with high reproducibility, accuracy and sensitivity. The three specific aims of this project are to map the global glycosylation alterations in the brains and blood of Alzheimer’s disease patients compared with controls, to characterize the site-specific changes in glycosylation of ApoE, and to document the effects of glycosylation changes on critical pathways involved in Alzheimer’s disease pathology. Importantly, the differences in glycosylation in AD will be mapped within each ApoE genotype, which will enable the discovery of precision medicine based solutions. Successful completion of this project will lead to the development of new glycosylation-based biomarkers for the early detection of Alzheimer’s disease and ApoE-specific targets for the development of novel therapeutics in AD.

项目摘要 阿尔茨海默氏病（AD）是一种令人衰弱的神经退行性疾病，在患病率目的地正在增长 几十年来投资诊断和治疗的研究和开发。因为很高 医疗保健伯恩和广告对认知功能和生活质量的毁灭性影响，早期的生物标志物 预防和治疗广告的疾病和干预措施是公共卫生的重点。寻找生物标志物和 治疗已转向糖生物学，这是对蛋白质和脂质附着的复杂糖的研究。职位 - 蛋白质和脂质的转化糖基化在许多关键生物过程中起作用 包括细胞到细胞通信和信号传导以及蛋白质结构和功能。最近，专业 糖基化的改变已在大脑，脑脊液和AD患者的血液中进行了记录 甚至在高级认知下降开始之前。糖基化可能意外参与AD，因此 测量血液中的糖基化是发现早期生物标志物的有前途的策略。载脂蛋白e （APOE）是AD的最大遗传危险因素。 APOE4同工型的载体增加了4-12倍 根据APOE4的副本数量，可能开发AD，并发展多达20种 几年前。 APOE是一种糖基化蛋白，几乎所有涉及的蛋白质，载体和受体 它的代谢也是糖基化的。 APOE的结构严重影响其功能。糖基化是 已知可以改变蛋白质结构，但要么是APOE的糖基化，也可以改变大脑的总体糖基化 在阿尔茨海默氏病患者中，血液中已经充分表征了 测量糖基化的精确分析工具已成为进步的技术障碍。我们的小组 是否开创了高级和敏感的液相色谱 - 质谱法的发展 作为精确测量数百种脂质和蛋白质的糖基化改变的工具。 我们的方法是快速通量，可以监视场地特异性，结构特异性和链接特异性 在数百个临床样品中的所有附着的糖中，具有较高的可重复性，准确性和敏感性。这 该项目的三个具体目的是绘制大脑和血液中全球糖基化的改变 与对照组相比，阿尔茨海默氏病患者的患者特异性特异性糖基化变化 apoe，并记录糖基化变化对阿尔茨海默氏症涉及的关键途径的影响 疾病病理学。重要的是，AD中的糖基化差异将在每个APOE中映射 基因型，将能够发现基于精确医学的解决方案。成功完成 项目将导致开发新的基于糖基化的生物标志物，以便早期发现 阿尔茨海默氏病和APOE特异性靶标，用于开发AD的新疗法。