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

阿尔茨海默病中脑源性蛋白质的外泌体转运至血液

• 批准号: 9564296
• 负责人: Jing Zhang
• 金额: $ 75.38万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9564296
• 关键词: Address; Affect; Alzheimer' s Disease; 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; Development; Diagnostic Sensitivity; Diagnostic Specificity; Disease; Disease Progression; Foundations; Future; Hippocampus (Brain); Human; Individual; Investigation; Mediating; Membrane; Methodology; Midbrain structure; Monitor; Mus; Nerve Degeneration; Nervous system structure; Neural Cell Adhesion Molecule L1; Neuraxis; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Patients; Performance; Plasma; Play; Protein Export Pathway; Protein Isoforms; Proteins; Proteomics; Publications; Reporting; Rodent Model; Role; Sampling; Serum; Severity of illness; Societies; Sorting - Cell Movement; Source; Surface; Synaptic Vesicles; Techniques; Technology; Testing; Therapeutic; Transportation; Vesicle; alpha synuclein; base; cell type; diagnostic accuracy; disability; disease diagnosis; disorder control; exosome; experimental study; human subject; improved; in vivo; intercellular communication; nanoparticle; nanoscale; new technology; novel; prion-like; single molecule; tau Proteins; tau-1; tool

Summary Growing evidence suggests that exosomes, a class of 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). Specially, 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 exosomes. Additionally, exosomes 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 exosomes may cross the blood-brain barrier (BBB), though the transportation mechanism remains unclear, but also that blood-based but CNS-specific exosomal 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 exosome surface markers specific to AD-related neuronal subpopulations or brain regions to identify more CNS- and AD- specific exosome markers, and in parallel adapt our nanoparticle sorting and single-molecule quantification technologies to enable high-purity isolation of CNS-derived exosomes in plasma and high-precision quantification of proteins in such exosomes to address several major challenges in the current field. Using the currently known (e.g., L1CAM) and more CNS- and AD- specific, CNS-derived exosomal surface markers, as well as the existing and further developed exosome isolation and quantification technologies, we will then compare AD- related biomarkers in L1CAM-containing exosomes or those from AD-related neuronal subpopulations in blood plasma from human patients, focusing on the performance of classic AD proteins and known exosomal candidates, specifically, Aβ, tau, α-synuclein, and their various isoforms; additional novel targets may be studied when necessary. For the verified AD-related exosomal 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，外泌体是一类膜囊泡，可以由 大多数细胞类型介导细胞间通讯，在启动和/或 特别是，已经证明细胞与细胞之间存在阿尔茨海默病（AD）的进展。 β 淀粉样蛋白 (Aβ)、tau 蛋白和其他与 AD 发病机制密切相关的蛋白质的转移 AD 病理在中枢神经系统 (CNS) 内的类似朊病毒的传播是介导的 至少部分通过外泌体，此外，外泌体携带独特的、疾病特异性的和 具有重要功能的货物可在体内的血液、脑脊液 (CSF) 和其他物质中检​​测到 最近，我们和其他人不仅证明了外泌体可以穿过体液。 血脑屏障（BBB），虽然运输机制仍不清楚，但也表明 基于血液但中枢神经系统特异性的外泌体分子可以成为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，我们将首先使用我们先进的蛋白质组学。 筛选 AD 相关神经亚群特有的外泌体表面标记物的技术或 识别更多 CNS 和 AD 特异性外泌体标记的大脑区域，并同时适应我们的 纳米颗粒分选和单分子定量技术，可实现高纯度分离 血浆中 CNS 衍生的外泌体以及此类外泌体中蛋白质的高精度定量 使用当前已知的（例如，L1CAM）和解决当前领域的几个主要挑战。 更多 CNS 和 AD 特异性、CNS 衍生的外泌体表面标志物，以及现有的和 进一步发展的外泌体分离和定量技术，我们将比较 AD- 含有 L1CAM 的外泌体或 AD 相关神经元的相关生物标志物 人类患者血浆中的亚群，重点关注经典 AD 的表现 蛋白质和已知的外泌体候选物，特别是 Aβ、tau、α-突触核蛋白及其各种 同种型；必要时可以研究其他新靶标以验证 AD 相关性。 外泌体蛋白，我们将进一步检查它们在动物模型中的纵向变化并探索 它们在细胞中从大脑转运到血液（例如穿过血脑屏障）的机制 动物模型以及改变它们作为未来 AD 治疗新目标的潜在方法。 拟议的实验可能会为廉价且广泛的研究奠定基础 此外，还提出了一系列研究，以帮助 AD 诊断和/或疾病追踪。 是阐明潜在有毒物质的新潜在清除途径的重要的第一步 CNS 蛋白质种类，最终可能为治疗解决问题提供关键机会 与 AD 神经变性相关的病理学。