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Dysregulation of Multivesicular Body and Exosome Flux in Alzheimer's Disease

阿尔茨海默病中多泡体和外泌体通量的失调

基本信息

批准号：
10213490
负责人：
ZIXU MAO
金额：
$ 211.87万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10213490
关键词：
Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease patient Amoeba genus Amyloid beta-Protein Automobile Driving Autophagocytosis Autophagosome Autopsy Biogenesis Brain Diseases Cell membrane Cell physiology Cells Complex Contracts Data Defect Degenerative Disorder Dictyostelium Disease Endoplasmic Reticulum Event Exocytosis Extracellular Space Functional disorder Genes Golgi Apparatus Health Human Impairment Laboratories Lipids Lysosomes Mammalian Cell Mediating Membrane Membrane Proteins Molecular Multivesicular Body Nerve Degeneration Neuraxis Neurodegenerative Disorders Neurofibrillary Tangles Neurons Organelles Parkinson Disease Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Peripheral Phenotype Process Protein Secretion Proteins RNA Rattus Regulation Research Role Senile Plaques Signal Transduction Source Specimen Stress Transgenic Animals Transgenic Organisms VAPA gene Vacuole Vesicle abeta oligomer base biological adaptation to stress cell type effective therapy exosome extracellular induced pluripotent stem cell intercellular communication microvesicles nervous system disorder neuron loss novel relating to nervous system response social stressor tau Proteins trafficking vesicular release

项目摘要

Alzheimer's disease (AD) is a progressive and degenerative disorder of the brain. It is pathologically characterized by amyloid β (Aβ) plaques, neurofibrillary tangles (NFTs), and loss of neurons. The key events driving the pathogenesis in AD are not completely understood. The long-term objective of my research is to understand the molecular and cellular processes by which neurons respond to stress and how dysfunction of these responsive mechanisms contributes to neurodegenerative process. We propose to investigate a new molecular regulator of exosome biogenesis and its role in AD pathogenesis. Exosomes are extracellular microvesicles secreted by cells. Exosomes carry cargos including proteins, lipids, and RNAs to influence or alter the phenotype of the target cells. Exosomes may spread toxic molecules related to AD such as Aβ, APP, and tau. Modulating the level of exosomes has been shown to alter the load of Aβ plaques. Some of the basic components involved in exosome biogenesis are known and highly related to the endocytic pathway. The intraluminal vesicles (ILVs) of multivesicular bodies (MVBs) are the cellular source of exosomes. As MVBs fuse with the plasma membrane, ILVs are released into the extracellular space as exosomes. In contrast to studies on exosome cargos in AD, little is known if and how exosome biogenic machinery itself may be altered in response to the AD related pathogenic stress. We have studied the endosomal-lysosomal pathways including autophagy in neural stress response and their roles in neurodegenerative diseases, particularly AD and Parkinson's disease. With these efforts, we have unexpectedly discovered a novel role for vacuole membrane protein 1 (VMP1), which was previously shown to regulate autophagy peripheral cells, in exosome biogenesis in neural cells and its involvement in AD. Our preliminary findings support strongly the new hypothesis that VMP1 regulates the flux of MVB-exosome and -lysosome network in neurons. AD-associated pathogenic stress increases VMP1 to promote exosome biogenesis, and this impacts the ability of donor and recipient neurons to handle stress. We propose to use molecular as well as cellular approaches, AD transgenic animal, and postmortem human specimens to determine in Aim I whether VMP1 controls the flux of endosomal and lysosomal network and exosome biogenesis in neurons, and its underlying molecular mechanisms; in Aim II whether VMP1-mediated regulation of exosome biogenesis is altered in neurons under AD associated pathogenic stress; in Aim III whether dysregulation of VMP1-mediated exosome biogenesis occurs and underlies neuronal stress and pathology in a transgenic rat model of AD; and in Aim IV the status of VMP1 pathway in postmortem human AD brains. The study will significantly advance our understanding of the molecular mechanisms regulating exosome formation and reveal how the exosome biogenic process is targeted by AD associated stressors and its involvement in AD pathogenesis.

阿尔茨海默病（AD）是一种大脑进行性和退行性疾病。这是病理性的