阿尔茨海默病(AD)发病机理复杂，现有药物只能缓解病情，并不能延缓或阻止病情的恶化。突触可塑性下降在AD早期就已发生，是记忆障碍的主要原因。Aβ寡聚体与突触可塑性下降密切相关。LilrB2是Aβ的高亲和力受体，参与Aβ介导的突触可塑性下降。本项目提出阻断Aβ-LilrB2通路降低Aβ毒性，促进轴突再生的新策略，对AD治疗具有重要意义。前期研究中发现先导化合物LC05是LilrB2的高亲和性配体，表现出良好的抗AD作用并可促突触再生。在此基础上基于Aβ-LilrB2复合物晶体模型对LC05进行结构改造，构建成药性更好的疏水母核，采用柔性链接并引入富电子芳香环增加与结合位点作用，从而提高与LiLrB2的亲和力。通过细胞、动物和分子多个水平筛选获得活性更高、成药性更好的化合物，并总结构效关系。进一步探索通过LilrB2减少神经损伤，促进突触功能恢复的作用机制，为AD治疗提供新的途径和方法

AD is a chronic neurodegenerative disease that has been recognized as one of the most intractable medical problems with heavy social and economic costs. The current drugs for AD only temporary slowdown the loss of cognitive function, but unable to stop or reverse the progression of dementia. Soluble β-amyloid (Aβ) oligomers impair synaptic plasticity and cause synaptic loss associated with AD. It was reported that LilrB2 was a receptor for Aβ oligomers with high affinity. LilrB2 not only contributed to memory deficits present, but also mediated loss of synaptic plasticity. Thus, Aβ- LilrB2 interaction inhibitors(ALIs) might be a potential therapeutic strategy for Alzheimer’s disease. In our previous study, lead compound LC05 has been found as a high affinity ALIs with good axon regeneration activity and anti-AD activity. In this project, novel compounds will be designed and synthesized based on Aβ- LilrB2 crystal structure. These compounds are likely to have satisfactory activities of reversing synaptic loss and cognitive impairment in AD progression with their structural profiles and characterization of LilrB2 inhibitors. It is predictable that the breakthrough in our research will be crucial for the development of novel AD drugs and overcome the drawbacks of current agents.