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.

阿尔茨海默病（Alzheimer's disease，AD）是一种进行性和退行性的脑疾病。这是病态的 其特征在于淀粉样蛋白β（Aβ）斑块、神经元缠结（NFT）和神经元损失。的关键事件 驱动AD的发病机制尚未完全了解。我研究的长期目标是 了解神经元对压力做出反应的分子和细胞过程，以及神经元的功能障碍是如何发生的。 这些反应机制有助于神经变性过程。我们建议研究一种新的 外泌体生物合成的分子调节因子及其在AD发病机制中的作用。外来体是细胞外的 由细胞分泌的微泡。外泌体携带包括蛋白质、脂质和RNA的货物以影响或 改变靶细胞的表型。外泌体可以传播与AD相关的毒性分子，如Aβ，APP， 和tau。调节外泌体的水平已被证明可以改变Aβ斑块的负荷。的一些基本 参与外泌体生物发生的组分是已知的，并且与内吞途径高度相关。的 多泡体（MVB）的腔内囊泡（ILV）是外来体的细胞来源。随着MVB熔断 ILV与质膜一起作为外泌体释放到细胞外空间。与研究相反， 关于AD中的外泌体货物，很少有人知道外泌体生物发生机制本身是否以及如何在AD中被改变。 对AD相关致病应激的反应。我们已经研究了内体-溶酶体途径，包括 神经应激反应中的自噬及其在神经退行性疾病，特别是AD和 帕金森氏症。通过这些努力，我们意外地发现了液泡膜的一个新作用， 蛋白1（VMP 1），以前被证明可以调节自噬外周细胞，在外来体生物发生 及其与AD的关系我们的初步发现有力地支持了新的假设， VMP 1调节神经元中MVB-外泌体和-溶酶体网络的流动。AD相关致病性 应激增加VMP 1以促进外泌体生物合成，这影响供体和受体的能力， 神经元来处理压力。我们建议使用分子和细胞方法，AD转基因动物， 和死后的人类标本，以确定目的I中是否VMP 1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 在AD相关的神经元中，VMP 1介导的外泌体生物发生调节是否改变 致病性应激;在目标III中，是否发生VMP 1介导的外泌体生物发生失调， 在AD的转基因大鼠模型中是神经元应激和病理学的基础;在目的IV中， 死后人类AD大脑中的通路。这项研究将大大促进我们对 调节外泌体形成的分子机制，并揭示外泌体生物发生过程是如何 AD相关应激源的靶向作用及其在AD发病机制中的作用。