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Exosomes:From biogenesis and secretion to the early pathogenesis of Alzheimer's disease

外泌体：从生物发生和分泌到阿尔茨海默病的早期发病机制

基本信息

批准号：
9421411
负责人：
Norman J Haughey
金额：
$ 40.88万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9421411
关键词：
APP-PS1 Abeta clearance Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid beta-Protein Amyloidosis Area Astrocytes Behavior Biogenesis Bioinformatics Biological Biological Markers Biological Neural Networks Biology Brain Caliber Cognitive Cognitive deficits Communication Complex Data Databases Dendritic Spines Environment Exhibits Functional disorder Glutamates Goals Growth Factor Impairment Individual Inflammatory Interleukin-1 beta Investigation Learning Lipids Lipoproteins Mediator of activation protein Memory MicroRNAs Modification Molecular Mus Nerve Degeneration Neural Pathways Neurites Neurobiology Neuroglia Neuronal Dysfunction Neuronal Plasticity Neurons Pathogenesis Pathology Pathway interactions Peptides Pre-Clinical Model Property Proteins Reporting Research Rodent Model Role Signal Pathway Signal Transduction Stimulus Stress Structure Synapses Systems Biology TNF gene Tauopathies Therapeutic Intervention Transgenic Model Vertebral column Vesicle Work base brain volume chemokine cytokine executive function exosome experimental study extracellular vesicles genome sequencing in vivo microvesicles nanovesicle neural circuit neuroinflammation neuroregulation neurotransmission neurotropic novel particle release factor repaired response synaptic function synaptogenesis tau Proteins tau-1 transcriptome whole genome

项目摘要

ABSTRACT Bi-directional communication between astrocytes and neurons regulates synaptic formation, synaptic strength, and participates in the regulation of neural circuitry by coordinating activity among groups of neurons. Astrocyte dysfunction in Alzheimer’s (AD), and other neurodegenerative conditions has been postulated to contribute to perturbations in activity of neural networks involved in memory and executive functions. Although AD associated modifications in the composition and quantity of various cytokine, chemokine and growth factors released from astrocytes have been demonstrated, these observations have thus far been insufficient to explain how astrocyte stress contributes to neuronal dysfunction. Advancements in our understanding of the biology of extracellular vesicles have begun to implicate glial released microvesicles as primary mediators of glia to neuron communication. In preliminary experiments we provide evidence that a variety of stimuli can induce astrocytes to shed microvesicles. The molecular cargo of these astrocyte-shed microvesicles was complex, and contained more than 200 distinct proteins, 100 miRNA, and hundreds of bioreactive lipid species. Moreover, the protein, miRNA and lipid composition of astrocyte exosomes was modified by the stimulus used to induce release and could be further modified by pre-treatment with oligomeric A peptides. These astrocyte- shed exosomes directly interacted with neurons to modify neuronal structure and function. Based on these preliminary findings we reasoned that a scientific focus on any one protein, lipid or miRNA would be unlikely to produce a true representation of the functions regulated by this complex signaling vesicles. Therefore, we used bioinformatic and systems biology approaches to understand how the protein, miRNA and lipid composition of exosomes interacts to regulate neuronal signaling pathways identified by whole genome sequencing of target neurons. In this application we focused our efforts on a small number of the identified pathways. In particular we concentrated on neural pathways associated with synapse formation, spine formation, and neurite outgrowth, as these neuronal structures are damaged in AD. The goals of this application are to understand how endogenous excitatory stimuli and inflammatory stimuli associated with AD modulate the cargo of astrocyte-shed exosomes and how these exosomes regulate/dysregulate the structure and function of target neurons.

摘要