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

痴呆相关蛋白病和神经炎症中的线粒体复合物 III 自由基

基本信息

批准号：
10617245
负责人：
ANNA GOLDSHMIDT ORR
金额：
$ 64.16万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10617245
关键词：
Address Aging Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Amyloid beta-Protein Astrocytes Biological Models Brain Brain Diseases Brain Pathology Cell Culture Techniques Cells Cellular Metabolic Process Coculture Techniques Cognitive deficits Complex Cytosol Data Dementia Disease Disease Progression Electron Transport Complex III Electrons Electrophysiology (science)Engineering Experimental Models Free Radicals Gene Expression Homeostasis Image Immune Impairment Individual Investigation Link Mediator Metabolism Mitochondria Modeling Molecular Mus Nerve Degeneration Neurodegenerative Disorders Neuroglia Neuroimmune Neuronal Dysfunction Neurons Neurophysiology - biologic function Oxidation-Reduction Oxidative Stress Pathogenicity Pathologic Pathology Pathway interactions Process Production Reactive Inhibition Reactive Oxygen Species Role Signal Transduction Site Synapses Tauopathies Testing Therapeutic Therapeutic Studies Transgenic Mice Transgenic Organisms Treatment Efficacy apolipoprotein E-4 behavior test beta amyloid pathology blood-brain barrier penetration drug development genetic manipulation hyperphosphorylated tau in vivo inhibitor insight interest mitochondrial dysfunction motor deficit mouse model neural neuroinflammation neuropathology novel novel therapeutic intervention pharmacologic pre-clinical predictive modeling protein misfolding research and development respiratory response sensor single-cell RNA sequencing small molecule tau Proteins tau dysfunction therapeutic evaluation tool transcriptomics translational study treatment strategy

项目摘要

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.

尽管人们对导致神经变性的各种致病机制的了解不断加深，目前尚无针对阿尔茨海默病 (AD) 或相关痴呆症的疾病缓解疗法。 AD 的主要影响因素，包括衰老、tau 蛋白病和 APP/淀粉样蛋白-β 病理学，与线粒体功能障碍是大脑中主要的能量产生者，但它们也可以产生能量。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和其他与衰老相关的疾病越来越多的证据表明线粒体活性氧的增加起到了痴呆症多种致病过程的中心前馈驱动因素，包括异常的细胞信号传导，然而，线粒体 ROS 的确切作用。由于目前可用工具的选择性和适用性较低，神经功能和病理学的研究尚不清楚。特别是，目前抑制 ROS 的工具对个体没有选择性。线粒体 ROS 产生的位点，可以破坏氧化还原稳态和细胞代谢。具有卓越选择性的线粒体 ROS 抑制剂可以产生新的机制见解和潜力我们最近发现了新的化合物，称为抑制剂。电子泄漏 (SEL) 的精确度独一无二：每种仅作用于线粒体中的单个目标并且只有当该目标产生 ROS 时，SEL 才会抑制线粒体 ROS 的产生而不阻碍能量。我们的初步结果表明，SEL 的目标是 ROS 的产生。线粒体呼吸复合物 III 可以改善 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。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在拟议的研究中，我们将确定针对复合物 III ROS 的 SEL 是否以及如何调节。不同 tau 蛋白病模型和 APP/Aβ 相关病理学中的神经胶质反应和神经元缺陷。复合物 III 的药理学和遗传操作以及多种方法，包括电生理学、转录组学和氧化还原成像，我们将测试复杂 III ROS 的新假设促进 tau 功能障碍和 hAPP/Aβ 引起的神经炎症级联反应和神经元损伤病理学（目标 1），复合物 III ROS 增加星形胶质细胞反应性和异常星形胶质细胞神经元通过增强星形胶质细胞中的免疫相关信号传导来相互作用（目标 2）。测试靶向复合物 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胶质细胞反应。位点选择性阻断线粒体 ROS 是减少神经退行性变的有效方法，并且揭示疾病中神经胶质和神经元损伤背后的新分子途径。