尽管针对ABeta的抗AD药物研发接连失败，ABeta对AD发生发展的贡献仍不可忽视。由于形态与病理功能的高度复杂性，全面遏制ABeta病理功能、促进其有效清除存在重大挑战。本项目提出基于ABeta聚集体重组与表面伪装的全新药物设计思路，通过构建多功能缀合物，将不同形态的ABeta重组共聚成相对单一形态。所形成的共聚体一方面将不再具有原聚集体表面特征，以降低其原有病理功能，规避其原有受损降解通路；另一方面，其所带的病原体模式分子可将共聚体伪装成类病原体颗粒，经特定模式受体激活机体固有免疫响应实现自身清除。此策略优势在于无需对原有复杂未明的病理通路进行逐一干预，可达到化繁为简的目的。我们已通过大量前期工作初步验证了其可行性。本项目将以此为基础，从结构优化、活性评价及机制解析三个主要方面，开展全面探索，以期发现新型有效的抗AD先导分子，并为基于此一创新机制的抗AD药物设计与开发提供基础。

Despite the successive failure of anti-AD drugs targeting Beta-amyloid protein (ABeta), the contribution of ABeta to AD cannot be ignored. However, owing to the high complexity of the morphology and pathological function of ABeta, it is still challenging to block the pathological function of ABeta and promote its effective clearance. In this project, a new strategy based on aggregate-reassembly and surface-camouflage is proposed. By constructing multi-functional conjugate, different forms of ABeta can be reconstituted into relatively single forms of co-aggregate, which the surface characteristics of original ABeta aggregates will be changed, resulting in the reduction of their original neurotoxicity and avoid their damaged degradation pathways; at the same time, the PAMP motif bearing ABeta co-aggregates will be recognized as pathogen-like particles by innate immune response of organisms through specific PRR, and be phagocytized to achieve self-clearance. The advantage of this strategy is that it can simplify the complexity of the original pathological pathways without one by one intervention. We have preliminarily verified its feasibility through a lot of preliminary work. Based on this, this project will carry out a comprehensive exploration from three main aspects: structure optimization, activity evaluation and mechanism analysis, in order to find new and effective anti-AD lead, and provide a key basis for the design and development of anti-AD drugs based on this innovative mechanism.