阿尔茨海默症（AD）迄今缺乏高效诊疗手段，而制约靶向AD发病主流学说——Aβ级联反应发病假说的干预策略研发的重要原因之一是缺乏对AD早期病理状态Aβ（e-Aβ，包括Aβ寡聚体/Aβ42）和活性分子关键互作序列的系统认识。本项目基于Aβ的KLVFF和CTF区域与e-Aβ识别和功能的关联性线索，拟应用与Aβ的KLVFF和CTF区域分别具有相互作用的已报道和项目负责人前期发现的荧光小分子为探针，结合截短体策略和丙氨酸突变策略开展Aβ的KLVFF和CTF区域分别与e-Aβ成像和/或毒性抑制的关联性验证，并构建基于e-Aβ的关键互作序列的活性小分子发现平台，并研发具备体内外药效的新型双重互作诊疗小分子。本项目首次结合应用化学生物学和生物物理学等手段系统比较和阐明e-Aβ成像/毒性抑制关键互作序列，并且多层次、多维度策略研发双重互作诊疗小分子，有望为实现靶向e-Aβ的AD的早期诊断和干预提供新的策略。

Alzheimer's disease (AD) is lack of efficient clinical treatment at present, and one of the key reasons that restrict the development of intervention strategy of Aβ cascade hypothesis, which is the mainstream theory of AD, is the lack of systematic understanding of Aβ (e-Aβ, including Aβ oligomer / Aβ42) and the key interaction sequence of active fraction in the early pathological state of AD. This project is based on the clue of correlation between KLVFF and CTF regions of Aβ and e-Aβ recognition and function. Several reported fluorescent small molecules that have interaction with KLVFF and CTF regions of Aβ was found as probes, and carried out the correlation verification between KLVFF and CTF regions of Aβ and e-Aβ imaging and / or toxicity inhibition respectively by combining the truncated body strategy and alanine mutation strategy, Small molecule discovery platform based on the key interaction sequence of e-Aβ was constructed, and a new double interaction diagnosis and treatment small molecule with in vitro and in vivo efficacy was developed. For the first time, this project systematically compares and clarifies the key interaction sequence of e-Aβ imaging / toxicity inhibition by means of Applied Chemical Biology and Biophysics, and develops a multi-level and multi-dimensional strategy to develop dual interaction of theranotic small molecules, which is expected to provide a new strategy for early diagnosis and intervention of AD targeting e-Aβ.