阿尔茨海默氏病（Alzheimer’s Disease, AD）是发病人数最多的神经退行性疾病，近期针对淀粉样蛋白聚集和沉积的药物研发均宣告失败，研究者开始积极寻找新的早期药物调控靶点。突触功能障碍被公认为AD早期病理变化，有报道线粒体与突触功能损伤密切相关，但机制尚不清楚。我们前期聚焦于线粒体分裂融合的动力学过程对此进行了初步研究，发现AD模型神经元中出现线粒体过度分裂、功能障碍以及突触功能损伤。而通过阻断动力相关蛋白1（Drp1）可抑制线粒体过度分裂，发挥突触保护作用。据此我们提出设想：Drp1介导的线粒体过度分裂造成动力学失衡是AD疾病中突触损伤的关键因素，通过抑制线粒体过度分裂，可阻断突触功能损伤，进而保护学习记忆功能。本研究将阐明线粒体动力学平衡调控突触功能的作用及详细机制，并明确其在学习记忆中的保护作用。本研究将为揭示神经元突触损伤的分子机制、寻找新型AD治疗药物提供实验依据。

Alzheimer’s disease (AD) is the most common neurodegenerative disease in the world. Recent research and development of drugs for AD that targeting Aβ deposit have all failed. This situation has urged the researchers to find new ideas of drug development. It has been shown that synaptic degeneration is the earliest pathological change of AD, so protecting synapses might prevent the progressive nature of this disease. Recent research has revealed that mitochondrial dysfunction is involved in the synaptic degeneration but the underlying mechanisms are poorly understood. Our preliminary research focused on mitochondrial dynamics and the data shows that there is abnormal mitochondrial fission in the AD model neurons, indicated by increased mitochondrial dysfunction and reduced mitochondrial distribution in synapses. Inhibiting mitochondrial fission through inhibiting Drp1 (dynamin-related protein 1) significantly protects synaptic function. So we hypothesize that mitochondrial dynamics imbalance is the key factor that leads to synaptic dysfunction. Correcting mitochondrial dynamics imbalance by inhibiting Drp1 could improve mitochondrial function, increase mitochondrial distribution in synapses and maintain synaptic function. Thus regulating mitochondrial dynamics might be a new approach for AD drug development. This project will focus on identifying the mechanism whereby mitochondrial dynamics regulating synaptic degeneration and its role in learning and memory function. The proposed studies will reveal the molecular mechanism of neuronal synaptic degeneration and provide new ideas for AD drug development.