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

摘要 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)--受影响的大脑。阿尔茨海默病的记忆障碍是脑部病理的一种表现 如淀粉样蛋白-β多肽(A-β)积聚和线粒体损伤。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。通过轴突运输将线粒体有效地运输到突触 对于维持适当的突触线粒体密度和能量是必不可少的，以便 维持突触活动；因此，轴突运输受损可能会影响突触传递。 抢救这种伤害的潜在机制和策略仍然难以捉摸。Miro1，a 线粒体外膜上的Rho-GTP酶，在促进 线粒体轴突运输与维持突触活性和神经元存活。有缺陷的 在果蝇中，miro1耗尽了突触终末线粒体的供应，并增强了 神经退行性变。然而，miro1在Aβ和AD诱导的线粒体转运中的作用， 阿尔茨海默病和阿尔茨海默病患者的淀粉样蛋白病理、神经炎症、突触和认知功能障碍 链接的老鼠模型仍未被探索。没有报告显示Miro1的表达发生了变化 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 线粒体功能障碍与神经炎症和突触损伤以及神经元的获得 Miro1可减轻淀粉样蛋白病变以及突触和认知功能障碍，并减缓 阿尔茨海默病的疾病进展。我们假设神经元Miro1介导的线粒体 功能障碍导致Aβ积聚和神经炎症，导致突触 退化和认知衰退。这项提议的目标是对这一角色有新的见解 MIRO1在AD发病机制中的作用，主要集中在Aβ堆积/清除，淀粉样蛋白病理， 线粒体功能和线粒体转运神经炎症，以及突触功能， 利用新型转基因Miro1/AD小鼠模型及神经元培养 随着神经元中Miro1水平的变化，以及含有线粒体的人类神经细胞衍生 来自AD和年龄匹配的正常受试者。该项目的成果可以呈现给Miro1 作为限制淀粉样蛋白病变和维持线粒体的潜在新治疗靶点 和突触的完整性，从而阻止AD的进展。

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.