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:10259729
- 负责人:
- 金额:$ 62.47万
- 依托单位:
- 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:
- 关键词:
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.
尽管越来越了解导致神经变性的各种致病机制,但
目前尚无治疗疾病的治疗方法,可用于阿尔茨海默氏病(AD)或相关痴呆症。
AD的主要因素,包括衰老,Tauopathy和App/App/淀粉样蛋白-β病理学,与
线粒体功能障碍。线粒体是大脑中的主要能量生产商,但也可以产生
过多的自由基或活性氧(ROS),这是AD中潜水员病理级联的基础
和其他与衰老有关的疾病。积累的证据表明,线粒体ROS的增加充当
痴呆症中潜水员致病过程的中央,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。但是,线粒体ROS的确切作用
在神经功能和病理学中,由于当前可用工具的选择性低和适合性,因此尚不清楚
机械和治疗研究。特别是,当前抑制ROS的工具对个体没有选择性
线粒体ROS产生的部位,可能会破坏氧化还原稳态和细胞代谢。新测试
线粒体ROS抑制剂具有较高的选择性可以产生新型的机械见解和潜力
疾病改良的AD治疗策略。我们最近发现了新颖的化合物,称为抑制剂
电子泄漏(SEL)的精确度是独一无二的:每一个仅作用于线粒体中的单个目标
只有当该目标产生ROS时。 SEL抑制线粒体ROS的产生而不会阻碍能量
和潜水模型系统中的代谢。我们的初步结果表明靶向ROS产生的SEL
从线粒体呼吸道复合物中III可以改善与AD相关的神经病理学和神经炎症
体内,调节原代细胞中星形胶质性反应性和星形胶质性神经元相互作用。但是,确切的
这些作用的机制尚不清楚,萨尔斯在不同蛋白质病中的有效性需要进一步
投资。在拟议的研究中,我们将确定靶向复合物III ROS的框架是否以及如何调节
在不同模型和APP/Aβ相关病理的不同模型中的神经胶质反应和神经元缺乏。使用
复合物III的药理和遗传操作以及潜水员的方法,包括
电生理学,转录组学和氧化还原成像,我们将测试复杂的III ROS的新假设
促进由Tau功能障碍和HAPP/Aβ引起的神经炎性级联反应和神经元障碍
病理学(AIM 1),该复合物III ROS增加了星形胶质性反应性和异常星形胶质性神经元
通过增强星形胶质细胞中与免疫相关的信号传导的相互作用(AIM 2)。拟议的研究一起将
测试是否靶向复合物III ROS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细胞反应。这些研究可以提供第一个证据
线粒体ROS的现场选择性封锁是减少神经变性的有效方法,并且
揭示了疾病中神经胶质和神经元损伤的新型分子途径。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
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数据更新时间:2024-06-01
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