Mitochondrial Complex III Free Radicals in Dementia-Related Proteinopathy and Neuroinflammation

尽管对导致神经变性的各种致病机制的理解越来越多， 目前没有可用于阿尔茨海默病（AD）或相关痴呆的疾病改善治疗。 AD的主要促成因素，包括衰老、tau蛋白病和APP/淀粉样蛋白-β病理学，与以下因素有关： 线粒体功能障碍线粒体是大脑中主要的能量生产者，但它们也可以产生 过量的自由基或活性氧（ROS），是AD中多种病理级联反应的基础 以及其他与衰老有关的疾病。越来越多的证据表明，增加线粒体活性氧作为一个 痴呆症中不同致病过程的中央前馈驱动器，包括异常细胞信号传导， 蛋白质错误折叠、神经炎症和神经元功能障碍。然而，线粒体活性氧的确切作用 在神经功能和病理学中的应用尚不清楚， 机制和治疗研究。特别地，目前用于抑制ROS的工具对于个体而言不是选择性的。 线粒体ROS产生的位点，并可破坏氧化还原稳态和细胞代谢。测试新 具有上级选择性的线粒体ROS抑制剂可以产生新的机制见解和潜力， 改善AD的疾病治疗策略。我们最近发现了新的化合物，称为抑制剂 电子泄漏（SELs），其精确性是独一无二的：每一个都只作用于线粒体中的一个目标 而且只有当目标产生活性氧时才能产生SEL抑制线粒体ROS产生而不阻碍能量 和代谢的不同模型系统。我们的初步结果表明，靶向ROS产生的SEL 线粒体呼吸复合物III改善AD相关的神经病理学和神经炎症 体内，并调节原代细胞中的星形胶质细胞反应性和星形胶质细胞-神经元相互作用。但具体 这些作用的机制尚不清楚，SEL在不同蛋白质病中的功效需要进一步研究。 调查在所提出的研究中，我们将确定靶向复合物III的SEL是否以及如何调节ROS， 神经胶质反应和神经元缺陷的不同模型的tau蛋白病和APP/A β相关的病理。使用 复合物III的药理学和遗传学操作以及各种方法，包括 电生理学，转录组学和氧化还原成像，我们将测试新的假设，复合物III活性氧 促进tau蛋白功能障碍和hAPP/A β引起的神经炎症级联反应和神经元损伤 复合物III ROS增加星形胶质细胞的反应性和异常星形胶质细胞-神经元的 通过增强星形胶质细胞中的免疫相关信号传导来增强相互作用（Aim 2）。拟议的研究将共同 测试靶向复合物III ROS是否可以减少与痴呆相关的多种类型的致病过程 并抑制促进疾病的异常星形胶质细胞反应。这些研究可以提供第一个证据 线粒体ROS的位点选择性阻断是减少神经变性的有效方法， 揭示了疾病中神经胶质和神经元损伤的新分子途径。

Despite a growing understanding of the various pathogenic mechanisms contributing to neurodegeneration, there are currently no disease-modifying treatments available for Alzheimer’s disease (AD) or related dementias. The main contributing factors in AD, including aging, tauopathy, and APP/amyloid-β pathology, are linked to mitochondrial dysfunction. Mitochondria are the main energy producers in the brain, but they can also generate excessive free radicals, or reactive oxygen species (ROS), which underlie diverse pathological cascades in AD and other aging-related disorders. Accumulating evidence suggests that increased mitochondrial ROS acts as a central, feed-forward driver of diverse pathogenic processes in dementia, including aberrant cell signaling, protein misfolding, neuroinflammation, and neuronal dysfunction. However, the exact roles of mitochondrial ROS in neural function and pathology are not clear due to low selectivity and suitability of currently available tools for mechanistic and therapeutic studies. In particular, current tools for inhibiting ROS are not selective for individual sites of mitochondrial ROS production and can disrupt redox homeostasis and cell metabolism. Testing of new mitochondrial ROS inhibitors with superior selectivity could generate novel mechanistic insights and potential disease-modifying treatment strategies for AD. We recently discovered novel compounds, termed Suppressors of Electron Leak (SELs), which are unique in their precision: each acts on only a single target in the mitochondria and only when that target is producing ROS. SELs inhibit mitochondrial ROS production without hindering energy and metabolism in diverse model systems. Our preliminary results suggest that an SEL targeting ROS production from mitochondrial respiratory complex III ameliorates AD-associated neuropathology and neuroinflammation in vivo, and modulates astrocytic reactivity and astrocytic-neuronal interactions in primary cells. However, the exact mechanisms of these effects are not known and the efficacy of SELs in different proteinopathies requires further investigation. In the proposed studies, we will determine if and how SELs targeting complex III ROS modulate glial responses and neuronal deficits in different models of tauopathy and APP/Aβ-associated pathology. Using pharmacological and genetic manipulations of complex III together with diverse approaches, including electrophysiology, transcriptomics, and redox imaging, we will test novel hypotheses that complex III ROS promotes neuroinflammatory cascades and neuronal impairments caused by tau dysfunction and hAPP/Aβ pathology (Aim 1), and that complex III ROS increases astrocytic reactivity and aberrant astrocytic-neuronal interactions by enhancing immune-related signaling in astrocytes (Aim 2). Together, the proposed studies will test if targeting complex III ROS can reduce multiple types of pathogenic processes associated with dementia and inhibit aberrant astrocytic responses that promote disease. These studies could provide the first evidence that site-selective blockade of mitochondrial ROS is an effective approach for reducing neurodegeneration, and reveal novel molecular pathways underlying glial and neuronal impairments in disease.