Mitochondrial modulation of neuroinflammation in AD and related tauopathies

AD 和相关 tau 病中神经炎症的线粒体调节

• 批准号: 10375646
• 负责人: Xinglong Wang
• 金额: $ 61.24万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2022-10-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10375646
• 关键词: Mitochondrial; modulation; neuroinflammation; AD; related

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.

项目摘要 阿尔茨海默病（AD）是老年人中最常见的痴呆，其特征在于神经元缠结， 老年斑和脑神经元的逐渐丧失。与老年斑相比， 与AD患者认知功能障碍的严重程度有更好的相关性。作为细胞内病变， 主要由过度磷酸化的微管相关蛋白tau组成。毫不奇怪的是， 已经投入了相当大的努力来开发基于tau的AD药物， 潜在的tau毒性在很大程度上仍然未知。线粒体功能障碍和神经炎症是 AD的早期病理学特征突出，并且越来越多地被认为是AD的关键因素 发病机制尽管线粒体功能障碍和神经炎症已被反复报道， 在tau蛋白病的动物模型中，它们之间相互作用的研究有限。有趣的是，在我们的初步研究中， 我们发现Mfn2，一种调节线粒体形态的线粒体外膜蛋白， 在广泛使用的PS19 tau转基因小鼠中， AD和相关的Tau蛋白病令人兴奋的是，Mfn2在神经元中的过表达足以显著地抑制神经元的生长。 抑制tau磷酸化、线粒体功能障碍、神经炎症、神经元损失和行为 PS19小鼠中的缺陷。此外，脂多糖诱导的神经炎症，甚至猝死， 也被神经元中Mfn2的过度表达大大抑制，这意味着神经元Mfn2是一个关键的 介导线粒体功能障碍和神经炎症。这些令人兴奋和有前途的初步 研究表明，详细调查Mfn2作为聚合点的潜在作用， 线粒体功能障碍和神经炎症在AD和相关Tau蛋白病中是必要的。使用新颖 转基因小鼠模型和一个有前途的合成治疗肽抑制Mfn2降解，这项研究 将不仅研究Mfn2是否以及如何调节线粒体功能障碍和神经炎症， 测试靶向Mfn2作为针对tau毒性的新型治疗方法的可行性。Tau病理学是一种 各种主要神经退行性疾病的突出共同组织病理学特征，包括但不限于 仅限于AD。我们提出的Mfn2及其在线粒体功能障碍中的会聚作用的研究， 神经炎症将具有非常广泛的科学和转化意义。