Regulation of Mitochondrial Quality Through Mitophagy in Alzheimer's Disease

描述（由申请人提供）：阿尔茨海默病（AD）是一种与年龄相关的进行性神经退行性疾病，影响了惊人比例的老龄人口，并导致记忆丧失和认知能力下降。目前，540万美国人患有AD，这是我们社会的一个主要健康问题。线粒体是细胞能量发电厂，其提供ATP以驱动神经元功能和存活所必需的各种生物活动。活体AD患者的影像学研究显示， 疾病阶段。线粒体功能障碍和氧化应激发生在AD动物模型的早期。缺陷线粒体的积累是家族性和散发性AD的特征，并且在AD病理生理学的早期起重要作用。突触线粒体功能障碍被认为是AD早期突触改变的关键因素。线粒体自噬是一种用于清除受损线粒体的货物特异性自噬-溶酶体途径，构成线粒体质量控制中的关键细胞途径。最近的研究表明，PINK 1/Parkin介导的途径确保线粒体的完整性和功能，从而防止功能障碍的线粒体的积累。然而，一个长期存在的问题是线粒体自噬过程本身是否被AD起始机制靶向以损害突触线粒体的常规消除，从而对起始突触病理学做出关键贡献。我们最近揭示了帕金森介导的线粒体自噬的独特功能，以消除受损的线粒体通过自噬-溶酶体途径在活的成熟皮层神经元。我们以前建立了Snapin，动力蛋白马达适配器，通过协调晚期内体和神经元中晚期内体-溶酶体运输的逆行运输来上调溶酶体功能。我们最近的研究揭示了AD神经元中改变的细胞通路：由于Snapin介导和动力蛋白驱动的逆行转运缺陷，底物蛋白水解受损。在当前的提案中，我们正在将分子、细胞生物学和长延时等多学科方法与多通道实时成像相结合，应用于AD模型衍生的成熟神经元中，并结合基因拯救实验。通过这些方法，我们将阐明AD神经元线粒体自噬和溶酶体缺陷的机制，以及它们对轴突线粒体质量控制的影响。这是与AD的早期病理生理学直接相关的关键动态细胞过程。提出了三个具体目标：目标1是在生理AD模型中建立线粒体自噬缺陷和线粒体病理之间的因果联系;目标2是确定溶酶体缺陷是否构成AD神经元中线粒体质量控制缺陷的核心方面;目标3是阐明挽救AD小鼠脑中线粒体病理和突触丢失的操作机制。所确定的机制有望为开发新的保护和治疗策略提供基础，以克服AD和其他与线粒体功能障碍和自噬-溶酶体病理学相关的主要神经退行性疾病。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is an age-related progressive neurodegenerative disease that affects a staggering percentage of the aging population and causes memory loss and cognitive decline. Currently, 5.4 million Americans suffer from AD, which is a major health concern in our society. Mitochondria are cellular energy power plants that supply ATP to power various biological activities essential for neuronal function and survival. Imaging studies in living AD patients reveal mitochondrial deficits at early disease stage. Mitochondrial dysfunction and oxidative stress occur early in animal models of AD. Accumulation of defective mitochondria is a feature of both familial and sporadic AD and plays an early important role in AD pathophysiology. Dysfunction of synaptic mitochondria has been proposed as a key factor involved in early synaptic alterations in AD. Mitophagy, a cargo-specific autophagy-lysosomal pathway for removal of damaged mitochondria, constitutes a key cellular pathway in mitochondrial quality control. Recent studies indicate that PINK1/Parkin- mediated pathways ensure mitochondrial integrity and function, thus preventing from the accumulation of dysfunctional mitochondria. However, a long-standing question is whether the mitophagy process itself is targeted by AD initiation mechanisms to impair routine elimination of synaptic mitochondria, and thereby make critical contributions to initiating synaptic pathology. We recently revealed unique features of Parkin-mediated mitophagy to eliminate damaged mitochondria via the autophagy-lysosomal pathway in live mature cortical neurons. We previously established that Snapin, a dynein motor adaptor, up-regulates lysosomal function by coordinating retrograde transport of late endosomes and late endosome-lysosomal trafficking in neurons. Our recent study uncovered an altered cellular pathway in AD neurons: an impaired substrate proteolysis due to the defects in Snapin-mediated and dynein-driven retrograde transport. In the current proposal, we are applying multidisciplinary approaches of molecular, cell biology, and long time-lapse with multi-channel live imaging in mature neurons derived from an AD model combined with gene rescue experiments. With these approaches, we will elucidate the mechanisms underlying mitophagy and lysosomal deficits in AD neurons, and their impact on quality control of axonal mitochondria. This is a key dynamic cellular process directly linked to early pathophysiology of AD. Three specific aims are proposed: Aim 1 is to establish a causative linkage between mitophagy deficit and mitochondrial pathology in a physiological AD model; Aim 2 is to determine whether lysosomal deficits constitute a core aspect of mitochondrial quality control deficiency in AD neurons; and Aim 3 is to elucidate operative mechanisms rescuing mitochondrial pathology and synapse loss in AD mouse brains. The identified mechanisms are expected to provide the basis for the development of novel protective and therapeutic strategies to overcome AD and other major neurodegenerative diseases associated with mitochondrial dysfunction and autophagy-lysosomal pathology.