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.

总结