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.

项目概要 阿尔茨海默病 (AD) 是一种使人衰弱的神经退行性疾病，尽管其患病率仍在不断上升 数十年来对诊断和治疗的研究和开发的投资。由于高 AD 对认知功能和生活质量的医疗负担和破坏性影响、AD 的早期生物标志物 疾病以及预防和治疗 AD 的干预措施是公共卫生的优先事项。寻找生物标志物和 治疗方法已转向糖生物学，即对附着在蛋白质和脂质上的复杂糖的研究。后- 蛋白质和脂质的翻译糖基化在许多关键的生物过程中发挥作用 包括细胞间通讯和信号传导，以及蛋白质结构和功能。近期，主要 AD 患者的大脑、脑脊液和血液中已记录到糖基化的改变 甚至在高级认知能力下降之前。糖基化可能与 AD 有因果关系，因此 测量血液中的糖基化是发现早期生物标志物的一种有前途的策略。载脂蛋白E (ApoE) 是 AD 的最大遗传风险因素。 ApoE4 同工型的携带者是其 4-12 倍 患 AD 的可能性取决于 ApoE4 的拷贝数，多达 20 个拷贝数就会患 AD 几年前。 ApoE 是一种糖基化蛋白，几乎所有参与 ApoE 的蛋白、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 已知会改变蛋白质结构，但既不会改变 ApoE 的糖基化，也不会改变大脑中的整体糖基化 由于缺乏阿尔茨海默氏病患者的血液中的 用于测量糖基化的精确分析工具一直是进步的技术障碍。我们组 率先开发了先进、灵敏的液相色谱-质谱方法 作为同时精确测量数百种脂质和蛋白质糖基化变化的工具。 我们的方法是快速通量的，可以监测位点特异性、结构特异性和连锁特异性 数百个临床样本中所有附着聚糖的分析，具有高重现性、准确性和灵敏度。这 该项目的三个具体目标是绘制大脑和血液中的整体糖基化变化图 阿尔茨海默病患者与对照组进行比较，以表征糖基化的位点特异性变化 ApoE，并记录糖基化变化对参与阿尔茨海默病的关键通路的影响 疾病病理学。重要的是，AD 中糖基化的差异将在每个 ApoE 中进行映射 基因型，这将使​​基于精准医学的解决方案的发现成为可能。顺利完成本次 该项目将导致开发新的基于糖基化的生物标志物，用于早期检测 阿尔茨海默病和 ApoE 特异性靶点，用于开发 AD 新型疗法。