阿尔茨海默病（AD）是最普遍的神经退行性疾病，造成巨大医疗、经济和社会问题。针对Aβ或Tau治疗AD的临床试验都以失败告终，提示存在被忽视或者未知的导致AD的重要机制。近期我们发现线粒体自噬缺陷导致线粒体清除障碍，造成受损线粒体在体内蓄积，与Aβ以及p-Tau协同诱导AD，并得到国内外同行广泛认可。但线粒体功能障碍在AD中的机制未明。故本项目科学假说是:神经元线粒体转运功能损伤介导PINK1/Parkin、NIX/BNIP3L或者其它线粒体自噬通路缺陷，导致Aβ和tau大量异常聚集，参与AD发生发展。本研究将从体内、体外以及临床方面，利用转基因线虫模型、iPSC诱导神经元和小胶质细胞共培养等技术，深入探讨神经元线粒体自噬缺陷参与AD机制;研究NAD+诱导的线粒体自噬改善AD的机制。这些研究有助于理解AD发病机制和研发抗AD药物，为改善AD预后提供新靶点，为AD早期诊断探索新标记物。

Alzheimer's disease (AD) is the most common neurodegenerative disease, causing formidable healthcare and socio-economic problems. The etiology of AD remains unclear, and continued failures in clinical trials on the treatment of AD targeting on Aβ or p-Tau suggesting the existence of other unknown causes of AD. Recent studies unveil severe mitochondrial dysfunction in postmortem AD patient brain tissues and in AD animal models. In 2017, we proposed a new etiology of AD: defective mitochondrial autophagy (mitophagy) leads to accumulation of damaged mitochondria, which synergizes with Aβ and p-Tau to induce AD; our 2019 original study verifies this hypothesis, but with the molecular mechanisms still elusive. Here, we further propose that in AD impaired neuronal mitochondrial motility causes defective mitophagy via impairment of the PINK1/Parkin, NIX/BNIP3L or other mitophagy pathways; we will further explore the mechanisms of NAD+-induced mitophagy in the treatment of AD. This study will employ in vitro, in vivo, and clinical data to explore novel mechanisms of defective neuronal mitophagy in AD by a combination of state-of-the-art techniques, including different transgenic nematode models and a novel system on co-culturing of iPSC-differentiated neurons and microglia. Exploration of the mechanisms of defective mitophagy in AD will enable further understanding of the pathogenesis of AD and will propel novel drug development. Our final aims are to provide a new target for improving the prognosis of AD patients, and to explore new biomarkers for early diagnosis of AD.