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（AD）是一种进行性和退行性的大脑疾病。这是病理性的 其特征是β淀粉样蛋白（Aβ）斑块、神经原纤维缠结（NFT）和神经元损失。关键事件 AD 发病机制尚不完全清楚。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功能障碍如何 这些反应机制有助于神经退行性过程。我们建议研究一个新的 外泌体生物合成的分子调节剂及其在 AD 发病机制中的作用。外泌体是细胞外的 细胞分泌的微泡。外泌体携带蛋白质、脂质和 RNA 等货物来影响或 改变靶细胞的表型。外泌体可能传播与 AD 相关的有毒分子，如 Aβ、APP、 和τ。调节外泌体的水平已被证明可以改变 Aβ 斑块的负载。一些基本的 参与外泌体生物发生的成分是已知的并且与内吞途径高度相关。这 多囊泡体（MVB）的腔内囊泡（ILV）是外泌体的细胞来源。作为 MVB 熔断器 ILV 通过质膜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，人们很少知道外泌体生物机制本身是否以及如何在 AD 中发生改变 对 AD 相关致病应激的反应。我们研究了内体-溶酶体途径，包括 自噬在神经应激反应中的作用及其在神经退行性疾病中的作用，特别是 AD 和 帕金森病。通过这些努力，我们意外地发现了液泡膜的新作用 蛋白 1 (VMP1)，此前已被证明在外泌体生物发生中调节自噬外周细胞 神经细胞及其与 AD 的关系。我们的初步研究结果有力地支持了新假设： VMP1 调节神经元中 MVB-外泌体和-溶酶体网络的流量。 AD相关致病性 压力会增加 VMP1 以促进外泌体生物合成，这会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， 和死后人类标本以确定目标 I 中 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分子机制；在目标二中 AD 相关神经元中 VMP1 介导的外泌体生物合成调节是否发生改变 致病应激；在目标 III 中，VMP1 介导的外泌体生物合成是否发生失调，以及 AD 转基因大鼠模型中神经元应激和病理学的基础；目标 IV 中 VMP1 的状态 死后人类 AD 大脑中的通路。这项研究将极大地增进我们对 调节外泌体形成的分子机制并揭示外泌体生物过程是如何进行的 AD 相关应激源的靶向及其参与 AD 发病机制。