Regulation of Mitochondrial Quality Through Mitophagy in Alzheimer's Disease

描述(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，影响到惊人比例的老龄化人口，并导致记忆力丧失和认知能力下降。目前，有540万美国人患有阿尔茨海默病，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，为神经元的功能和生存所必需的各种生物学活动提供ATP。活体阿尔茨海默病患者的影像研究显示早期线粒体缺陷 疾病阶段。线粒体功能障碍和氧化应激在阿尔茨海默病动物模型早期发生。线粒体缺陷堆积是家族性和散发性AD的一个特征，在AD的早期病理生理学中起着重要作用。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。有丝分裂是一种货物特异性的自噬-溶酶体途径，用于去除受损的线粒体，是线粒体质量控制的关键细胞途径。最近的研究表明，PINK1/Parkin介导的通路确保了线粒体的完整性和功能，从而防止了功能障碍的线粒体的积累。然而，一个长期存在的问题是，吞噬有丝分裂过程本身是否被AD启动机制所针对，以破坏突触线粒体的常规消除，从而在启动突触病理中做出关键贡献。我们最近揭示了Parkin介导的有丝分裂吞噬的独特特征，通过自噬-溶酶体途径消除活的成熟皮质神经元中受损的线粒体。我们之前已经证实，作为动力蛋白运动适配器的Snapin，通过协调晚期内吞体内的逆行运输和晚期内切酶-溶酶体在神经元中的运输，上调溶酶体的功能。我们最近的研究揭示了AD神经元中一种改变的细胞途径：由于Snapin介导的和Dynein驱动的逆行运输的缺陷，底物蛋白降解受损。在目前的方案中，我们正在应用分子、细胞生物学和长时间推移的多通道实时成像的多学科方法在成熟神经元中进行成像，该成像来自于AD模型结合基因拯救实验。通过这些方法，我们将阐明AD神经元有丝分裂和溶酶体缺陷的潜在机制，以及它们对轴突线粒体质量控制的影响。这是一个关键的动态细胞过程，直接与AD的早期病理生理学有关。提出了三个具体的目标：目标1是在生理性AD模型中建立线粒体吞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小鼠脑内线粒体病理和突触丢失的操作机制。这些已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.