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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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos 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

项目摘要

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.

总结