阿尔茨海默病（AD）发病与遗传因素密切相关，家族性AD集中体现了AD的病理生理特点，是研究AD发病机制的理想人群。PSEN1是家族性AD最为常见的致病基因，我们在前期工作中对其进行了长期和深入研究，发现淀粉样蛋白（Aβ）寡聚体是PSEN1基因突变导致AD发病的关键蛋白，然而Aβ寡聚体是否为AD的早期关键致病因素及其致病机制仍需进一步研究。本项目将利用前期工作中已建立的独特PSEN1突变转基因小鼠模型，寻找Aβ寡聚体中致病的分子形式，明确其细胞和亚细胞分布，揭示其生成和清除途径，找出阻断其细胞毒性的关键干预手段；同时，利用已建立的家族性AD队列，阐明Aβ寡聚体从痴呆前阶段发展到痴呆阶段的动态演变规律，揭示Aβ寡聚体在这一过程中的致病作用。本项目将完善和验证“Aβ寡聚体致病假说”，找到遏制甚至逆转AD发生发展的药物靶点，为药物研发提供新的思路。

Genetic factors play an important role in the development of Alzheimer’s disease (AD). Familial AD gathers the core pathophysiology of AD, and is an ideal study population for AD research. PSEN1 is the most common causative gene in familial AD on which we have been studing for a long time, and we found that it greatly influenced on the production and clearence of amyloid β (Aβ) oligomers which we belived it was crucial proteins involved in the pathogenesis of AD. However, we don’t know how early it involves in the AD development and whether it is a trigger at a very early stage for the disease. Our project will explore the molecular identity of Aβ oligomer, clarify its cellular and subcellular distribution in the brain, analyse its generation and the way to scavenge for it, and use three key interventions blocking its potential cytotoxic pathway, based on our established PSEN1 transgenic mice model and several transfected cell lines. Meanwhile, we will make certain what a role the Aβ oligomers plays in the pathogenesis of familial AD members who carry the PS1 mutaiton from pre-dementia phase to dementia phase in our established familial AD cohort.The goal of this project will verify “Aβ oligomers hypothesis”, and find potential therapeutic targets, and provide a strong basis for the development of novel medcines.