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

尽管人们对导致神经退变的各种致病机制的了解越来越多， 目前还没有针对阿尔茨海默病(AD)或相关痴呆症的疾病修正治疗方法。 AD的主要致病因素，包括衰老、肌萎缩侧索硬化症和APP/淀粉样蛋白-β病理，与 线粒体功能障碍。线粒体是大脑中的主要能量产生者，但它们也可以产生 过量的自由基或活性氧物种(ROS)，是AD各种病理级联的基础 以及其他与衰老相关的疾病。越来越多的证据表明，线粒体ROS增加起到了 痴呆不同致病过程的中央前馈驱动因素，包括细胞信号异常， 蛋白质错误折叠、神经炎症和神经元功能障碍。然而，线粒体ROS的确切作用 在神经功能和病理学方面，由于目前可用的工具选择性和适用性较低，因此尚不清楚 机械学和治疗学研究。具体地说，当前用于抑制ROS的工具对个体没有选择性 线粒体产生ROS的部位，并可破坏氧化还原动态平衡和细胞代谢。测试新的 线粒体ROS抑制剂具有优越的选择性，可以产生新的机制洞察力和潜力 阿尔茨海默病的疾病修正治疗策略。我们最近发现了一种新的化合物，称为抑制物 电子泄漏(SEL)，它们在精度上是独一无二的：每个SEL只作用于线粒体中的一个靶点 而且只有在目标产生ROS的情况下。SEL在不阻碍能量的情况下抑制线粒体ROS生成 以及在不同模型系统中的新陈代谢。我们的初步结果表明，针对ROS产生的SEL 线粒体呼吸复合体III改善AD相关神经病理和神经炎症 并调节原代细胞中星形胶质细胞的反应性和星形胶质细胞与神经元的相互作用。然而，准确的 这些作用的机制尚不清楚，SELS对不同蛋白质病的疗效还需要进一步研究 调查。在拟议的研究中，我们将确定靶向复合体III ROS的SEL是否以及如何调节ROS 不同动物模型的神经胶质反应和神经元缺失与APP/Aβ相关病理。vbl.使用 复合体III的药理和遗传操作以及各种方法，包括 电生理学、转录学和氧化还原成像，我们将测试新的假设，即复合体III ROS 促进tau功能障碍和HAPP/Aβ引起的神经炎性级联反应和神经元损伤 病理学(目标1)，以及复合体III ROS增加星形胶质细胞的反应性和异常的星形胶质细胞-神经元 通过增强星形胶质细胞中免疫相关信号的相互作用(目标2)。总而言之，拟议的研究将 测试靶向复合体III ROS是否可以减少与痴呆相关的多种致病过程 并抑制促进疾病的异常星形细胞反应。这些研究可以提供第一个证据 这种对线粒体ROS的选择性阻断是减少神经变性的有效方法，并且 揭示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.