REGULATION OF MITOCHONDRIAL QUALITY THROUGH MITOPHAGY IN ALZHEIMER'S DISEASE

项目摘要 阿尔茨海默病（AD）影响50%的85岁以上的个体，并且AD的广泛影响是 摧毁了老龄化人口及其家庭--这一健康问题可能最好通过早期治疗来解决。 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、活性氧生成减少、代谢减退，以及 改变线粒体动力学和运输。数据支持AD患者显示早期生物能量和 在出现任何组织病理学或临床特征之前，代谢紊乱。因此，线粒体 这些缺陷可能是早期的，并且对于AD病理学的发作和发展是关键的。线粒体质量 因此，控制成为AD的中心问题，并且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， 线粒体质量控制途径，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降解。我们提供了第一个神经成像 证据显示在活神经元中帕金森介导的线粒体自噬的独特特征。我们的工作进一步揭示了 帕金森介导的线粒体自噬在早期AD疾病阶段被强烈激活，但受损的清除 线粒体缺陷是溶酶体蛋白酶缺陷的结果，其阻碍降解。 神经元通讯的关键线粒体位于突触处。突触紊乱 线粒体是AD的早期病理事件。AD的一个显著特征是突触 线粒体吞噬体-含有线粒体的自噬体的积累。由于帕金森介导 线粒体自噬主要发生在神经元的索马体，差距在我们的理解如何突触的质量 线粒体的控制，以及突触线粒体缺陷是否归因于线粒体自噬 因此，必须解决AD中触发早期突触失效的调节异常。线粒体自噬控制线粒体 质量和数量，最近被提出作为一个重要的机制，调节能量代谢。一 关于线粒体自噬和线粒体能量活动交叉的性质的长期问题， 神经元仍有待解决。我们的项目旨在：1）建立线粒体自噬与 生理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量功能障碍。 我们的研究将促进对AD发病机制中关键早期步骤的理解。因此，我们的发现可能 为治疗AD和正常认知功能减退提供了新的分子和药理学靶点。

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.