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Neuronal mitochondrial transport-linked neuroinflammation and amyloid pathology in Alzheimer's disease

阿尔茨海默病中神经元线粒体转运相关的神经炎症和淀粉样蛋白病理学

基本信息

批准号：
10467803
负责人：
Shirley ShiDu Yan
金额：
$ 196.27万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-05 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10467803
关键词：
Address Affect Age Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease therapeutic Amyloid Amyloid beta-Protein Axonal Transport Behavioral Blood Platelets Brain Brain Pathology Cell Line Cells Cerebrum Cognitive DLG4 gene Defect Disease Progression Down-Regulation Drosophila genus Functional disorder Goals Human Hybrids Immune Impaired cognition Impairment In Vitro Inflammasome Inflammatory Inflammatory Response Injury Innate Immune Response Lead Learning Link Maintenance Mediating Mediator of activation protein Memory Memory impairment Microglia Mitochondria Mitochondrial DNA Mitochondrial Diseases Molecular Mus Natural Immunity Nerve Degeneration Neurons Outcome Outcome Study Outer Mitochondrial Membrane Oxidative Stress Pathogenesis Pathologic Pathology Patients Pattern Pattern recognition receptor Phagocytosis Pilot Projects Play Presynaptic Terminals Production Regulation Reporting Role Signal Transduction Synapses Synapsins Synaptic Transmission Synaptosomes Therapeutic Agents Transgenic Mice Transgenic Organisms abeta accumulation aged amyloid pathology density follow-up genetic manipulation human model improved in vivo insight mitochondrial dysfunction mouse model neuroinflammation neuronal survival new therapeutic target novel novel therapeutics protective effect response rho GTP-Binding Proteins synaptic function synaptic pruning trafficking transcription factor

项目摘要

Summary Mitochondrial dysfunction and synaptic damage are early pathological features of the Alzheimer’s disease (AD)-affected brain. Memory impairment in AD is a manifestation of brain pathologies such as the accumulation of amyloid-β peptide (Aβ) and mitochondrial damage. Synaptic mitochondria are early targets of Aβ and are more vulnerable to Aβ-induced mitochondrial and synaptic dysfunction. Efficient mitochondrial trafficking to synapses, via axonal transport, is essential for the maintenance of proper synaptic mitochondrial density and energy in order to sustain synaptic activity; thus, impaired axonal transport may compromise synaptic transmission. The underlying mechanisms and strategies to rescue such injury remain elusive. Miro1, a mitochondrial Rho-GTPase on the mitochondrial outer membrane, plays a vital role in facilitating mitochondrial axonal transport and sustaining synaptic activity and neuronal survival. Defective Miro1 in Drosophila depletes the supply of mitochondria in synaptic terminals, and enhances neurodegeneration. However, the role of Miro1 on Aβ- and AD-induced mitochondrial trafficking, amyloid pathology, neuroinflammation, and synaptic and cognitive dysfunction in AD and AD- linked mouse models remains unexplored. There is no report showing altered expression of Miro1 in Alzheimer’s brain. It is unclear whether neuronal Miro1 is a mechanistic linker between mitochondrial dysfunction and neuroinflammation and synaptic injury and if gaining of neuronal Miro1 could alleviate amyloid pathology and synaptic and cognitive dysfunction and slow down disease progression in AD. We hypothesize that neuronal Miro1-mediated mitochondrial dysfunction contributes to Aβ accumulation and neuroinflammation, leading to synaptic degeneration and cognitive decline. The goal of this proposal is to gain new insights into the role of Miro1 in AD pathogenesis, focusing on Aβ accumulation/clearance, amyloid pathology, mitochondrial function and mitochondrial trafficking neuroinflammtion, and synaptic function, utilizing novel genetically manipulated transgenic Miro1/AD mouse models and neuronal culture with altered Miro1 levels in neurons, and human neuronal cells containing mitochondria derived from AD and normal aged-matched subjects. The outcomes of the project could present Miro1 as a potential new therapeutic target for limiting amyloid pathology and maintaining mitochondrial and synaptic integrity thereby halting AD progression.

概括线粒体功能障碍和突触损伤是阿尔茨海默病的早期病理特征疾病（AD）影响的大脑。 AD 中的记忆障碍是大脑病变的一种表现例如淀粉样β肽（Aβ）的积累和线粒体损伤。突触线粒体是 Aβ 的早期靶标，更容易受到 Aβ 诱导的线粒体和突触功能障碍。通过轴突运输，线粒体向突触的有效运输是对于维持适当的突触线粒体密度和能量至关重要，以便维持突触活动；因此，轴突运输受损可能会损害突触传递。挽救这种损伤的潜在机制和策略仍然难以捉摸。米罗1，一个线粒体 Rho-GTP 酶位于线粒体外膜上，在促进线粒体轴突运输和维持突触活动和神经元存活。有缺陷的果蝇中的 Miro1 耗尽突触末端线粒体的供应，并增强神经变性。然而，Miro1 对 Aβ 和 AD 诱导的线粒体运输的作用， AD 和 AD 中的淀粉样蛋白病理学、神经炎症、突触和认知功能障碍链接的小鼠模型仍未被探索。没有报告显示 Miro1 的表达发生改变在阿尔茨海默氏症的大脑中。目前尚不清楚神经元 Miro1 是否是两者之间的机械连接器线粒体功能障碍、神经炎症和突触损伤以及神经元的获得 Miro1 可以缓解淀粉样蛋白病理、突触和认知功能障碍并减缓 AD 的疾病进展。我们假设神经元 Miro1 介导的线粒体功能障碍会导致 Aβ 积累和神经炎症，从而导致突触退化和认知能力下降。该提案的目标是获得对该角色的新见解 Miro1 在 AD 发病机制中的作用，重点关注 Aβ 积累/清除、淀粉样蛋白病理学、线粒体功能和线粒体运输神经炎症和突触功能，利用新型基因操纵转基因 Miro1/AD 小鼠模型和神经元培养神经元中 Miro1 水平发生改变，以及含有线粒体的人类神经元细胞来自 AD 和正常年龄匹配受试者。该项目的成果可以展示 Miro1 作为限制淀粉样蛋白病理和维持线粒体的潜在新治疗靶点和突触完整性，从而阻止 AD 进展。