β淀粉样蛋白（Aβ）来源的可扩散性配体（ADDLs）被认为是阿尔茨海默病（AD）的核心致病因子。ADDLs可以通过削弱N-甲基-D-天冬氨酸受体（NMDAR）的功能损害突触可塑性并导致认知功能障碍。最近研究发现ADDLs可以和海马神经元表面的受体酪氨酸激酶EphB2结合，触发EphB2被蛋白酶体降解，进而破坏NMDAR正常功能的发挥。本申请拟采用包括非天然氨基酸标记法在内的生化手段详细研究ADDLs和EphB2的相互作用位点，据此设计干扰二者相互作用的小肽，并在分子、细胞和整体水平上研究干扰小肽对ADDLs神经毒性的保护作用。本项目的完成将会促进靶向ADDLs抗AD药物的设计和开发。

Amyloid-beta derived diffusible ligands (ADDLs) are thought to be the key pathogenic factors in Alzheimer's disease (AD). ADDLs can cause the decrease of synapse plasticity and cognitive disorder by affecting the function of N-methyl-D-aspartic acid receptor (NMDAR). It is recently found that ADDLs can bind the receptor tyrosine kinase EphB2 on the surface of hippocampus neurons and trigger the degradation of EphB2 by proteosome, thereby impairing NMDAR's normal functioning. This research proposal aims at identifying the interaction sites between ADDLs and EphB2 by utilizing biochemical methods including the use of non-natural amino acid probes, based on which to develop small peptides to interfer with the interaction between ADDLs and EphB2, and then investigate the propective effects of interfering small peptides on ADDLs neurotoxity at molecular, celluar and organismic levels. The accomplishment of this research project will facilitate the development of drugs to treat AD.