Pink1, amyloid pathology, and mitochondrial quality control in Alzheimer's Disease

线粒体和突触功能障碍是阿尔茨海默病(AD)的早期病理特征 大脑。生物能量学功能紊乱，呼吸衰竭，线粒体动力学异常，以及 在大脑和周围组织中观察到活性氧物种(ROS)的水平，包括血小板 阿尔茨海默病患者。淀粉样蛋白-β肽(A-β)对线粒体和突触功能有不良影响。这个 修复这种伤害的潜在机制和战略仍不清楚。PTEN诱导的可能的蛋白激酶1 (PINK1)对于维持线粒体的完整性和通过赋予抗性进行质量控制是重要的 氧化应激和毒性侮辱，调节适当的线粒体动力学，并通过消除和 通过有丝分裂去除受损的线粒体。到目前为止，PINK1在淀粉样蛋白病理和Aβ-1中的作用 诱导的线粒体和突触缺陷是未知的。我们假设PINK1功能受损 与AD的淀粉样蛋白病理发展相关的慢性Aβ积聚 线粒体和突触变性。这项提案的目标是对 PINK1在AD发病机制中的作用，主要关注Aβ的堆积/清除、淀粉样蛋白病理、线粒体质量 控制(功能、动力学、线粒体清除)和突触功能，利用PINK1的基因传递 技术，新型转基因PINK1/AD小鼠模型和神经元培养 阿尔茨海默病和阿尔茨海默病的神经元和含有线粒体的神经细胞中PINK1水平的变化 年龄匹配的正常受试者。该项目的成果可能会使PINK1成为一种潜在的新技术 限制淀粉样蛋白病变并维持线粒体完整性从而阻止AD的治疗靶点 进步。

Mitochondrial and synaptic dysfunction is early pathological features of the Alzheimer’s disease (AD)-affected brain. Perturbed bioenergetics function, respiration failure, aberrant mitochondrial dynamics, and increased levels of reactive oxygen species (ROS) are observed in brains and peripheral tissues including platelets of subjects with AD. Amyloid-β peptide (Aβ) has deleterious effects on mitochondrial and synaptic function. The underlying mechanisms and strategies to repair such injury remain unclear. PTEN-induced putative kinase 1 (PINK1) is important for the maintenance of mitochondrial integrity and quality control by conferring resistance to oxidative stress and toxic insults, modulating proper mitochondrial dynamics, and by eliminating and removing damaged mitochondria via mitophagy. So far, the role of PINK1 in amyloid pathology and Aβ- induced mitochondrial and synaptic defects is unexplored. We hypothesize that impairment of PINK1 function contributes to chronic Aβ accumulation relevant to the development of amyloid pathology in AD and to mitochondrial and synaptic degeneration. The goal of this proposal is to gain new insights into the role of PINK1 in AD pathogenesis, focusing on Aβ accumulation/clearance, amyloid pathology, mitochondrial quality control (function, dynamics, mitochondrial clearance), and synaptic function, utilizing gene delivery of PINK1 technology, novel genetically manipulated transgenic PINK1/AD mouse models and neuronal culture with altered PINK1 levels in neurons, and human neuronal cells containing mitochondria derived from AD and normal aged-matched subjects. The outcomes of the project could present PINK1 as a potential new therapeutic target for limiting amyloid pathology and maintaining mitochondrial integrity thereby halting AD progression.