REGULATION OF MITOCHONDRIAL QUALITY THROUGH MITOPHAGY IN ALZHEIMER'S DISEASE

项目总结 阿尔茨海默病(AD)影响着50%的85岁以上的人，其广泛的影响是 对老龄化人口及其家庭的毁灭性打击--这是一个健康问题，最好的办法是及早解决 干预策略。高度流行的阿尔茨海默病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，低代谢，以及 改变了线粒体的动力学和运输。数据支持AD患者表现出早期的生物能量和 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 缺陷可能是AD病理发生和发展的早期和关键因素。线粒体质量 因此，控制成为AD的一个中心问题，也是疾病早期干预的明确靶点。 神经元如何维持高质量的线粒体？有丝分裂，一种特定于货物的自噬，构成了一个关键 线粒体质量控制的途径，包括将老化或受损的线粒体隔离到 自噬小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 显示帕金介导的活神经元有丝分裂吞噬的独特特征的证据。我们的工作进一步揭示了 在阿尔茨海默病的早期阶段，Parkin介导的有丝分裂反应被强烈激活，但损害了对 有缺陷的线粒体是溶酶体蛋白酶缺乏的结果，这阻止了降解。 对神经元通讯至关重要的线粒体位于突触。突触障碍 线粒体是阿尔茨海默病的早期病理事件。AD的一个显著特征是突触 线粒体--含有线粒体的自噬小体的堆积。自从帕金调停以来 吞丝现象主要发生在神经元的胞体中，这是我们对突触质量如何理解的空白 线粒体受到控制，以及突触线粒体缺陷是否归因于有丝分裂 在AD中引发早期突触失败的调节失调必须得到解决。有丝分裂控制线粒体 并被认为是调节能量代谢的一种重要机制。一个 关于有丝分裂和线粒体能量活动的交集的性质的长期问题 神经元仍有待解决。我们的项目旨在：1)在有丝分裂之间建立因果联系 生理性AD模型中的缺陷和早期突触病理；2)定义策略的机械性细节 这可以挽救AD小鼠的吞丝分裂功能缺陷和生物能量障碍。 我们的研究将促进对AD发病机制的一个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新的分子和药理靶点。

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.