Mitochondrial modulation of neuroinflammation in AD and related tauopathies

项目摘要 阿尔茨海默病(AD)是老年人最常见的痴呆症，以神经原纤维缠绕为特征， 老年斑和脑神经元进行性丧失。与老年斑相比，神经原纤维缠结 与AD患者认知功能障碍的严重程度有较好的相关性。作为细胞内病变，神经原纤维 主要由过度磷酸化的微管相关蛋白tau组成。毫不奇怪，相当可观 人们一直致力于基于tau的AD药物的开发，尽管tau的致病机制 毒性在很大程度上仍不清楚。线粒体功能障碍和神经炎症是早期突出的 阿尔茨海默病的病理特征，已日益被认为是AD发病的关键因素。 尽管线粒体功能障碍和神经炎症在动物模型中被反复报道 在变态病中，对其相互作用的研究有限。有趣的是，我们在初步研究中发现， 线粒体外膜蛋白Mfn2调节线粒体形态及其与细胞因子的关系 在广泛使用的PS19 tau转基因小鼠中，内质网显著减少，与AD及相关 紧张症。令人兴奋的是，Mfn2在神经元中的过度表达足以显著抑制tau PS19的磷酸化、线粒体功能障碍、神经炎症、神经元丢失和行为障碍 老鼠。此外，内毒素引起的神经炎症甚至猝死也可能大大 Mfn2在神经元中的过度表达抑制，共同暗示神经元Mfn2是两者的关键介质 线粒体功能障碍和神经炎症。这些令人兴奋和有希望的初步研究表明 Mfn2作为线粒体功能障碍的汇聚点的潜在作用的详细研究 阿尔茨海默病和相关疾病中的神经炎症是有根据的。使用新的转基因小鼠模型和 作为一种有前景的合成治疗多肽，抑制Mfn2的降解，这项研究不仅将研究是否和 Mfn2如何调节线粒体功能障碍和神经炎症，但也测试了靶向的可行性 Mfn2作为一种新的治疗方法对抗tau毒性。Tau病理是一种突出的常见疾病 各种主要神经退行性疾病的组织病理学特征，包括但不限于AD。我们的 对Mfn2及其在线粒体功能障碍和神经炎症中的汇聚作用的拟议研究将 具有非常广泛的科学和翻译意义。

Project Summary Alzheimer's disease (AD) is the most common dementia in the elderly characterized by neurofibrillary tangles, senile plaques and a progressive loss of brain neurons. Compared with senile plaques, neurofibrillary tangles have a better correlation with the severity of cognitive impairment in AD. As intracellular lesions, neurofibrillary are largely composed of hyperphosphorylated microtubule-associated protein tau. Not surprisingly, considerable efforts have been devoted to tau-based AD drug development though the pathomechanism underlying tau toxicity remains largely unknown. Mitochondrial dysfunction and neuroinflammation are prominent early pathological features of AD and have been increasingly implicated as critical factors for AD pathogenesis. Despite both mitochondrial dysfunction and neuroinflammation have been repeatedly reported in animal models of tauopathies, there is limited study of their interplay. Interestingly, in our preliminary studies, we found that Mfn2, the mitochondrial outer membrane protein regulating mitochondrial morphology and association with endoplasmic reticulum, was significantly reduced in the widely used PS19 tau transgenic mice for AD and related tauopathies. Excitingly, the overexpression of Mfn2 in neurons is sufficient to remarkably suppress tau phosphorylation, mitochondrial dysfunction, neuroinflammation, neuronal loss and behavioral deficits in PS19 mice. In addition, lipopolysaccharide-induced neuroinflammation and even sudden death could also be greatly suppressed by overexpressing Mfn2 in neurons, together implying neuronal Mfn2 as a crucial mediator for both mitochondrial dysfunction and neuroinflammation. These exciting and promising preliminary studies suggest that a detailed investigation into the potential role of Mfn2 as a point of convergence for mitochondrial dysfunction and neuroinflammation in AD and related tauopathies is warranted. Using novel transgenic mouse models and a promising synthetic therapeutic peptide inhibiting Mfn2 degradation, this study will not only study whether and how Mfn2 regulates mitochondrial dysfunction and neuroinflammation, but also test the feasibility of targeting Mfn2 as a novel therapeutic approach against tau toxicity. Tau pathology is a prominent common histopathological feature of various major neurodegenerative diseases including but not limited to AD. Our proposed studies of Mfn2 and its convergent role in mitochondrial dysfunction and neuroinflammation will have very broad scientific and translational significance.