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

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 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。

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.