REGULATION OF MITOCHONDRIAL QUALITY THROUGH MITOPHAGY IN ALZHEIMER'S DISEASE

阿尔茨海默病中通过线粒体自噬调节线粒体质量

• 批准号: 10414056
• 负责人: Qian Cai
• 金额: $ 52.5万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10414056
• 关键词: Address; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Autophagocytosis; Autophagosome; Axonal Transport; Bioenergetics; Cell physiology; Cessation of life; Clinical; Communication; Data; Defect; Development; Disease; Early Intervention; Energy Metabolism; Event; Family; Functional disorder; Generations; Glycolysis; Goals; Health; Homeostasis; Human; Image; Impaired cognition; Impairment; Individual; Intervention; Life; Link; Lysosomes; Mediating; Metabolic; Metabolic dysfunction; Metabolism; Mitochondria; Mitochondrial Diseases; Molecular; Mus; Nature; Neurodegenerative Disorders; Neurons; Oxidative Phosphorylation; Parkin; Pathogenesis; Pathologic; Pathologic Processes; Pathology; Pathway interactions; Patients; Peptide Hydrolases; Pharmacology; Physiological; Play; Positioning Attribute; Presynaptic Terminals; Preventive; Process; Production; Quality Control; Reaction; Reactive Oxygen Species; Regulation; Research; Role; SNAPIN gene; Signal Transduction; Stress; Synapses; Testing; Therapeutic; Work; age related neurodegeneration; aged; aging population; base; design; high risk; human very old age (85+); in vivo; insight; mitochondrial metabolism; mouse model; neuronal cell body; novel; synaptic failure; therapy design

PROJECT SUMMARY Alzheimer’s disease (AD) affects 50% of individuals over 85 years old, and the broad impact of AD is devastating the aging population and their families—a health problem that is likely best addressed with early intervention strategies. The earliest features of the highly prevalent AD have been linked to mitochondrial abnormalities, including reduced energy production, reactive oxygen species generation, hypometabolism, and altered mitochondrial dynamics and transport. Data support that AD patients display early bioenergetic and metabolic disruptions prior to the emergence of any histopathological or clinical features. Thus, mitochondrial deficits are likely early and critical for the onset and development of AD pathology. Mitochondrial quality control, then, emerges as a central problem in AD and is a clear target point for early interference in disease. How do neurons maintain high quality mitochondria? Mitophagy, a cargo-specific autophagy, constitutes a key pathway of mitochondrial quality control that involves sequestration of aged or damaged mitochondria into autophagosomes and subsequent degradation within lysosomes. We provided the first neuronal imaging evidence showing unique features of Parkin-mediated mitophagy in live neurons. Our work further revealed that Parkin-mediated mitophagy is robustly activated at early AD disease stages, but impaired clearance of defective mitochondria is a result of lysosomal protease deficiency, which blocks degradation. Mitochondria critical for neuronal communication are situated at the synapse. The disturbance of synaptic mitochondria is a proposed early pathological event in AD. A distinctive feature of AD is the synaptic accumulation of mitophagosomes—autophagosomes containing mitochondria. Since Parkin-mediated mitophagy mainly occurs in the soma of neurons, the gap in our understanding of how the quality of synaptic mitochondria is controlled, and whether synaptic mitochondrial deficits are attributed to mitophagy dysregulation to trigger early synaptic failure in AD, must be addressed. Mitophagy controls mitochondrial quality and quantity, and was recently proposed as an important mechanism regulating energy metabolism. A long-standing question on the nature of the intersection of mitophagy and mitochondrial energetic activity in neurons remains to be addressed. Our project is designed to: 1) establish a causative link between mitophagy deficits and early synaptic pathology in a physiological AD model; 2) define mechanistic details of a strategy that can rescue mitophagy deficiency and bioenergetic dysfunction in AD mice. Our studies will advance understanding of a critical early step in AD pathogenesis. As such, our findings may provide new molecular and pharmacological targets for treating AD and normal cognitive decline.

项目概要 阿尔茨海默病 (AD) 影响 50% 的 85 岁以上老年人，AD 的广泛影响是 给老龄化人口及其家庭带来毁灭性的打击——这个健康问题最好尽早解决 干预策略。高度流行的 AD 的最早特征与线粒体有关 异常，包括能量产生减少、活性氧产生、代谢减退和 改变线粒体动力学和运输。数据支持 AD 患者表现出早期生物能和 在出现任何组织病理学或临床特征之前代谢中断。因此，线粒体 缺陷可能是 AD 病理的早期发生和发展的关键。线粒体质量 因此，控制成为 AD 的核心问题，也是疾病早期干预的明确目标点。 神经元如何维持高质量的线粒体？线粒体自噬是一种货物特异性自噬，是细胞自噬的关键 线粒体质量控制的途径，涉及将老化或受损的线粒体隔离到 自噬体和随后在溶酶体内的降解。我们提供了第一个神经元成像 证据显示活神经元中帕金介导的线粒体自噬的独特特征。我们的工作进一步揭示了 Parkin 介导的线粒体自噬在 AD 疾病早期被强烈激活，但线粒体自噬的清除受损 线粒体缺陷是溶酶体蛋白酶缺乏的结果，溶酶体蛋白酶缺乏会阻碍降解。 对神经元通讯至关重要的线粒体位于突触处。突触紊乱 线粒体被认为是 AD 的早期病理事件。 AD 的一个显着特征是突触 线粒体自噬体的积累——含有线粒体的自噬体。由于帕金介导 线粒体自噬主要发生在神经元体中，我们对突触质量如何影响的理解存在差距 线粒体受到控制，突触线粒体缺陷是否归因于线粒体自噬 必须解决引发 AD 早期突触衰竭的失调问题。线粒体自噬控制线粒体 质和量，最近被提出作为调节能量代谢的重要机制。一个 关于线粒体自噬和线粒体能量活动交叉本质的长期存在的问题 神经元仍有待解决。我们的项目旨在：1）建立线粒体自噬之间的因果关系 生理性 AD 模型中的缺陷和早期突触病理学； 2）定义策略的机制细节 可以挽救 AD 小鼠的线粒体自噬缺陷和生物能功能障碍。 我们的研究将增进对 AD 发病机制关键早期步骤的了解。因此，我们的研究结果可能 为治疗 AD 和正常认知能力下降提供新的分子和药理学靶点。