Extracellular vesicle transport of brain-derived proteins to the blood in Alzheimer disease

阿尔茨海默病中细胞外囊泡将脑源性蛋白质转运至血液

• 批准号: 10031274
• 负责人: Min Shi
• 金额: $ 298.18万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10031274
• 关键词: Address; Affect; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Alzheimer’s disease biomarker; American; Amyloid beta-Protein; Animal Model; Animals; Biological Markers; Blood; Blood - brain barrier anatomy; Body Fluids; Brain; Brain region; Cell model; Cells; Central Nervous System Diseases; Cerebellum; Cerebrospinal Fluid; Clinical; Complex; Corpus striatum structure; Data; Diagnostic Sensitivity; Disease; Disease Progression; Foundations; Future; Hippocampus (Brain); Human; Individual; Investigation; Mediating; Membrane; Methodology; Midbrain structure; Monitor; Nerve Degeneration; Nervous system structure; Neural Cell Adhesion Molecule L1; Neuraxis; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Patients; Performance; Pilot Projects; Plasma; Play; Protein Export Pathway; Protein Isoforms; Proteins; Proteomics; Publications; Reporting; Rodent Model; Role; Sampling; Sensitivity and Specificity; Serum; Severity of illness; Societies; Sorting - Cell Movement; Source; Specificity; Surface; Synaptic Vesicles; Techniques; Technology; Testing; Therapeutic; Transportation; Vesicle; alpha synuclein; base; blood-brain barrier crossing; cell type; diagnostic accuracy; disability; disorder control; experimental study; extracellular vesicles; human subject; improved; in vivo; intercellular communication; nanoparticle; nanoscale; new technology; novel; prion-like; single molecule; tau Proteins; tau-1; tool; vesicle transport

Summary Growing evidence suggests that extracellular vesicles (EVs), membrane vesicles that can be secreted by most cell types to mediate intercellular communication, play important roles in the initiation and or progression of Alzheimer disease (AD). Specifically, it has been demonstrated that cell-to-cell transfer of amyloid beta (Aβ), tau, and other proteins critically involved in AD pathogenesis, as well as the prion-like propagation of AD pathology within the central nervous system (CNS) is mediated at least in part via EVs. Additionally, EVs carrying unique, disease- specific, and functionally important cargo are detectable in vivo in blood, cerebrospinal fluid (CSF) and other body fluids. More recently, we and others have demonstrated not only that EVs may cross the blood-brain barrier (BBB), though the transportation mechanism remains unclear, but also that blood-based but CNS-specific EV molecules can be a valuable source of biomarkers for neurodegenerative diseases, including AD. In this study, we will first use our advanced proteomics techniques to screen for EV surface markers specific to AD-related neuronal subpopulations or brain regions to identify more CNS- and AD- specific EV markers, and in parallel adapt our nanoparticle sorting and single-molecule quantification technologies to enable high-purity isolation of CNS-derived EVs in plasma and high-precision quantification of proteins in such EVs to address several major challenges in the current field. Using the currently known (e.g., L1CAM) and more CNS- and AD- specific, CNS-derived EV surface markers, as well as the existing and further developed EV isolation and quantification technologies, we will then compare AD-related biomarkers in L1CAM-containing EVs or those from AD-related neuronal subpopulations in blood plasma from human patients, focusing on the performance of classic AD proteins and known EV candidates, specifically, Aβ, tau, α-synuclein, and their various isoforms; additional novel targets may be studied when necessary. For the verified AD-related EV proteins, we will further examine their longitudinal changes in animal models and explore the mechanisms by which they are transported from the brain to blood (e.g., crossing BBB) in cellular and animal models and potential ways to alter them as novel future AD treatment targets. The proposed experiments will likely establish the foundation leading to an inexpensive and widely available test to aid in AD diagnosis and/or disease tracking. Additionally, the proposed set of studies is an important initial step toward elucidating a novel potential clearance pathway for potential toxic CNS protein species and ultimately it may provide critical opportunities for therapeutically addressing the pathology associated with neurodegeneration in AD.

概括 越来越多的证据表明细胞外蔬菜（EV），可以是膜蔬菜 大多数细胞类型分泌以介导细胞间的交流，在 阿尔茨海默氏病（AD）的启动和 /或进展。具体来说，已经证明了 淀粉样β（Aβ），TAU和其他与AD的细胞向细胞转移 发病机理以及中枢神经内的AD病理的ion样传播 系统（CNS）至少部分通过电动汽车介导。此外，携带独特的，疾病的电动汽车 - 特异性且在功能上重要的货物在血液，脑脊液（CSF）的体内可检测 和其他体液。最近，我们和其他人不仅证明了电动汽车可能 越过血脑屏障（BBB），尽管运输机制尚不清楚，但是 此外，基于血液但中枢神经系统特异性的EV分子可能是生物标志物的宝贵来源 神经退行性疾病，包括AD。在这项研究中，我们将首先使用先进的蛋白质组学 筛选特定于广告相关的神经元亚群或大脑的EV表面标记的技术 识别更多CNS和AD特定EV标记的区域，并并行适应我们的纳米颗粒 分类和单分子定量技术可以使CNS衍生的高纯度隔离 等离子体中的电动汽车和此类电动汽车中蛋白质的高精度量化以解决几个主要 当前领域的挑战。使用当前已知的（例如L1CAM）以及更多的CNS和AD- 特定的CNS衍生的EV表面标记以及现有的和进一步的EV隔离 然后，我们将比较含L1CAM的广告相关生物标志物 EV或来自人类患者血浆中与广告相关的神经元亚群的电动汽车， 专注于经典AD蛋白和已知EV候选者的性能，特别是Aβ，TAU， α-突触核蛋白及其各种同工型；必要时可以研究其他新型目标。为了 经过验证的与广告相关的EV蛋白，我们将进一步研究它们在动物中的纵向变化 模型并探索将它们从大脑传输到血液的机制（例如， 在细胞和动物模型中越过BBB）以及将其作为新颖的未来广告改变它们的潜在方法 治疗目标。拟议的实验可能会建立基础 廉价且可广泛可用的测试，以帮助AD诊断和/或疾病跟踪。另外， 提出的一组研究是阐明新型潜在清除率的重要第一步 潜在有毒中枢神经系统蛋白质物种的途径，最终可能为 在治疗上解决与AD中神经退行性相关的病理。