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

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

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.

总结 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）影响大脑。AD的记忆障碍是大脑病理的表现 如淀粉样β肽（Aβ）的积累和线粒体损伤。突触 线粒体是Aβ的早期靶点，更容易受到Aβ诱导的线粒体和 突触功能障碍线粒体通过轴突运输有效地运输到突触， 对于维持适当的突触线粒体密度和能量至关重要， 维持突触活性;因此，受损轴突运输可损害突触传递。 潜在的机制和策略，以挽救这种伤害仍然难以捉摸。米罗1 a 线粒体外膜上的线粒体Rho-GTdR在促进线粒体外膜的形成中起着至关重要的作用。 线粒体轴突运输和维持突触活动和神经元存活。缺陷 果蝇中的Miro 1耗尽突触末梢中线粒体的供应，并增强 神经变性然而，Miro 1在Aβ和AD诱导的线粒体运输中的作用， 淀粉样蛋白病理学，神经炎症，以及AD和AD中的突触和认知功能障碍， 连锁小鼠模型尚未开发。没有报告显示Miro 1的表达改变 在老年痴呆症的大脑中。目前尚不清楚神经元Miro 1是否是神经元之间的机械连接子。 线粒体功能障碍和神经炎症和突触损伤以及神经元的获得 Miro 1可以减轻淀粉样病变和突触及认知功能障碍， AD的疾病进展。我们假设神经元Miro 1介导的线粒体 功能障碍有助于Aβ积聚和神经炎症，导致突触 退化和认知能力下降。本提案的目标是获得对该角色的新见解 Miro 1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，以及突触功能， 利用新的遗传操作的转基因Miro 1/AD小鼠模型和神经元培养物 在神经元中Miro 1水平改变，含有线粒体的人类神经元细胞 AD和正常年龄匹配的受试者。该项目的成果可以展示Miro 1 作为限制淀粉样蛋白病理学和维持线粒体 和突触完整性从而阻止AD进展。