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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：
10030548
负责人：
ANNA GOLDSHMIDT ORR
金额：
$ 57.97万
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/10030548
关键词：
Address Aging Alzheimer&apos s Disease Amyloid beta-Protein Astrocytes Biological Models Blood - brain barrier anatomy Brain Brain Diseases Brain Pathology Cell Culture Techniques Cells Cellular Metabolic Process Cognitive deficits Complex Cytosol Data Dementia Disease Disease Progression Electron Transport Complex III Electrons Electrophysiology (science)Energy Metabolism Engineering Experimental Models Free Radicals Gene Expression Homeostasis Image Immune Impairment Individual Investigation Link Mediator of activation protein 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 Pharmacology Process Production 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 drug development genetic manipulation in vivo inhibitor/antagonist insight interest mitochondrial dysfunction motor deficit mouse model neuroinflammation neuropathology novel novel therapeutics pre-clinical predictive modeling protein misfolding relating to nervous system 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越来越多，