TOMM40-mediated mitochondrial dysfunction and Alzheimers disease

总结 线粒体功能障碍和突触损伤是脑梗死的早期病理特征， 阿尔茨海默病（Alzheimer's disease，AD）是一种影响大脑的疾病。Aβ对线粒体有有害作用， 突触功能障碍拯救这种损伤的潜在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发病机制中的作用。 线粒体Aβ的蓄积可能是导致 线粒体和神经元扰动。TOMM 40（外线粒体转位酶） 膜-40kD）是TOM复合物的关键亚基，是大量细胞的主要进入通道。 大多数输入的蛋白质必须通过才能进入线粒体内部。A多态性 inTOMM 40与迟发性AD的风险增加和认知功能下降相关 业绩48.这种多态性是唯一的核编码基因在遗传学中确定 迄今为止的研究，推测有助于负载相关的线粒体功能障碍。Aβ和 在体外细胞中APP可通过TOMM 40通道进入线粒体 然而，TOMM 40介导的Aβ输入机制仍不清楚， TOMM 40对淀粉样蛋白病理学、线粒体和突触变性的影响，以及 Aβ环境中的神经炎症尚未阐明。在试点研究中，我们观察到 TOMM 40敲除小鼠显示线粒体Aβ水平显著降低，沿着 在过表达Aβ的Tg mAPP小鼠中，线粒体和突触功能得到改善。 此外，Tg mAPP小鼠中TOMM 40水平的降低减弱了先天性免疫， 促炎反应这些数据表明，TOMM 40可能是重要的 在AD的线粒体淀粉样蛋白病理学中的作用。我们假设TOMM 40的功能受损 导致慢性线粒体Aβ积聚，与淀粉样蛋白病理学发展相关 导致线粒体和突触变性。该提案的目的是获得 TOMM 40在AD发病机制中作用的新见解，重点关注线粒体Aβ 积累/清除，淀粉样蛋白病理学，突触线粒体特性，氧化应激， 炎症和突触功能，利用一种新的遗传操作的转基因 TOMM 40/AD小鼠模型和具有改变的TOMM 40水平的神经元培养物（增加/减少） 在富含Aβ的环境中（整体和神经元TOMM 40的遗传缺陷和增加的 过表达Aβ的AD型转基因小鼠中的神经元TOMM 40）。该项目的成果 提示TOMM 40可能成为限制肿瘤生长的潜在新靶点， 线粒体淀粉样蛋白病理学，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. 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.