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

• 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
• 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' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' 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

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.

阿尔茨海默氏病（AD）是大脑的进行性和退化性疾病。它是病理 以淀粉样β（Aβ）斑块，神经纤维缠结（NFT）和神经元丧失为特征。关键事件 在AD中驱动发病机理尚不完全了解。我的研究的长期目标是 了解神经元对压力的反应以及如何功能障碍的分子和细胞过程 这些响应机制有助于神经退行性过程。我们建议调查一个新的 外泌体生物发生及其在AD发病机理中的作用的分子调节剂。外泌体是细胞外的 细胞分泌的微泡。外泌体携带包括蛋白质，脂质和RNA在内的碳的影响或 改变靶细胞的表型。外泌体可能传播与AD相关的有毒分子，例如Aβ，APP， 和tau。调节外泌体的水平已显示出改变Aβ斑块的载荷。一些基本 与外泌体生物发生有关的成分是已知的，并且与内吞途径高度相关。 多细胞体（MVB）的腔内蔬菜（ILV）是外泌体的细胞来源。作为MVBS保险丝 使用质膜，ILV作为外泌体释放到细胞外空间中。与研究相反 在AD中的外泌体货物上，鲜为人知是否以及外泌体生物机械本身如何改变 对AD相关的致病应力的反应。我们已经研究了内体 - 溶菌体途径，包括 神经应力反应的自噬及其在神经退行性疾病中的作用，尤其是AD和 帕金森氏病。通过这些努力，我们意外地发现了真空膜的新作用 蛋白1（VMP1）先前显示用于调节自噬外周细胞，在外泌体生物发生中 在神经细胞及其参与AD中。我们的初步发现支持了新的假设 VMP1调节神经元中MVB - 外观和溶质体网络的通量。广告相关的致病性 压力增加了VMP1以促进外泌体生物发生，这会影响供体和受体的能力 神经元处理压力。我们建议使用分子和细胞方法，AD转基因动物， 在目标I中确定VMP1是否控制内体和 神经元中的溶酶体网络和外泌体生物发生及其潜在的分子机制；在AIM II中 VMP1介导的外泌体生物发生的调节是否在AD相关的AD神经元中改变 致病应力；在AIM III中，是否发生VMP1介导的外泌体生物发生的失调和 AD的转基因大鼠模型中的神经元应力和病理基础；在AIM IV中，VMP1的状态 死后人类广告大脑中的途径。这项研究将大大提高我们对 调节外泌体形成的分子机制并揭示了外泌体生物源过程是如何的 由AD相关的应激源及其参与AD发病机理的靶向。