TOMM40-mediated mitochondrial dysfunction and Alzheimers disease

摘要 线粒体功能障碍和突触损伤是该病的早期病理特征 阿尔茨海默病(AD)累及大脑。β对线粒体和 突触功能障碍。抢救这种伤害的基本机制和策略仍然存在 不清楚。最近的研究强调了线粒体Aβ在AD发病中的作用。 线粒体Aβ积聚可能是导致高血压的始动病理事件 线粒体和神经元的扰动。TOMM40(外线粒体易位酶 膜-40kD)是TOM复合体的关键亚单位，是 大多数进口蛋白质必须通过才能进入线粒体内部。A多态 InTOMM40与晚发性AD风险增加和认知能力下降相关 表演48.这种多态是在遗传基因中发现的唯一核编码基因 到目前为止，研究推测这可能与负荷相关的线粒体功能障碍有关。一个β和 APP可以通过TOMM40通道进入体外细胞的线粒体 然而，TOMM40介导的Aβ导入机制及其影响仍不清楚 TOMM40对淀粉样蛋白病理、线粒体和突触变性的影响 Aβ环境中的神经炎症尚未阐明。在我们的初步研究中，我们观察到 TOMM40基因敲除小鼠的线粒体Aβ水平显著降低， 高表达Aβ的TG MAPP小鼠线粒体和突触功能改善。 此外，TGMAPP小鼠体内TOMM40水平的降低会减弱先天免疫和 促炎反应。这些数据表明，TOMM40可能具有潜在的重要性 在阿尔茨海默病的线粒体淀粉样变中。我们假设TOMM40的功能受损 与淀粉样变相关的慢性线粒体Aβ积聚 导致线粒体和突触变性。这项提议的目的是为了 线粒体β在AD发病机制中作用的新认识 堆积/清除，淀粉样蛋白病理，突触线粒体特性，氧化应激， 炎症和突触功能，利用一种新的基因操纵转基因 TOMM40/AD小鼠模型和TOMM40水平改变的神经元培养(得/失) 在富含β的环境中(遗传缺陷的全局和神经元TOMM40和增加 过表达Aβ的AD型转基因小鼠的神经元TOMM40)。该项目的成果 可能提出TOMM40可能是一个潜在的新的治疗靶点 线粒体淀粉样变性，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. Aβ has deleterious effects on mitochondrial and synaptic dysfunction. The underlying mechanisms and strategies to rescue such injury remain unclear. Recent studies have highlighted the role of mitochondrial Aβ in AD pathogenesis. Accumulation of mitochondrial Aβ may be an initiating pathological event leading to mitochondrial and neuronal perturbation. TOMM40 (Translocase of the Outer Mitochondrial Membrane-40kD) is the key subunit of the TOM complex, the main entry channel for the vast majority of imported proteins must pass to enter the mitochondrial interior. A polymorphism inTOMM40 is associated with an increased risk of late-onset AD and decreased cognitive performance48. This polymorphism is the only nuclear-encoded gene identified in genetic studies to date that presumably contributes to LOAD-related mitochondrial dysfunction. Aβ and APP can be imported into the mitochondria through the TOMM40 channel in an in vitro cell culture, however, the TOMM40-mediated Aβ import mechanism remains unclear and the impact of TOMM40 on amyloid pathology, mitochondrial and synaptic degeneration, and neuroinflammation in Aβ milieu have not yet been elucidated. In our pilot studies, we observed that TOMM40 knockdown mice displayed significantly reduced mitochondrial Aβ levels, along with improvement in mitochondrial and synaptic function in Tg mAPP mice overexpressing Aβ. Furthermore, reduced TOMM40 levels in Tg mAPP mice attenuate the innate immune and proinflammatory response. These data suggest that TOMM40 may potentially be of importance in mitochondrial amyloid pathology of AD. We hypothesize that impaired function of TOMM40 contributes to chronic mitochondrial Aβ accumulation relevant to developing amyloid pathology of AD, leading to mitochondrial and synaptic degeneration. The goal of this proposal is to gain new insight into the role of TOMM40 in AD pathogenesis, focusing on mitochondrial Aβ accumulation/clearance, amyloid pathology, synaptic mitochondrial properties, oxidative stress, inflammation, and synaptic function, utilizing a novel genetically manipulated transgenic TOMM40/AD mouse models and neuronal culture with altered TOMM40 levels (gaining/losing) in an Aβ-rich environment (genetic deficiency of global and neuronal TOMM40 and increased neuronal TOMM40 in AD-type transgenic mice overexpressing Aβ). The outcomes of the project could present that TOMM40 might be a potential new therapeutic target for limiting mitochondrial amyloid pathology thereby halting AD progression.