多肽SNP-9靶向调控CacyBP对阿尔茨海默病tau蛋白病变的作用及机理

阿尔兹海默病（AD）以Aβ和tau病变为主要病理特征，目前缺乏理想治疗手段，近年基于单靶标策略直接针对Aβ或tau设计的药物均未获得理想结果，抗AD新药研发亟需新思路。越来越多证据提示AD中Aβ和tau病变是相互影响并互为因果的两条独立途径，靶向单一途径策略可能始终对另一途径作用有限。本课题组前期研究发现一种具有独特作用机理的多肽SNP-9，可通过两条相互独立途径同时抑制Aβ和tau病变发挥抗AD作用，在多种AD动物模型显示出显著疗效，目前已阐明SNP-9抑制Aβ病变的机理，同时发现CacyBP可能是介导SNP-9抑制tau病变的关键分子，但其具体机制尚待阐明。本项目首先确证CacyBP在SNP-9抗AD中地位，同时解析SNP-9与CacyBP作用方式；进一步，分析SNP-9靶向CacyBP抗tau病变机制；阐明SNP-9抗AD机理，为抗AD新药研发提供候选分子，为AD靶点研究提供新思路。

Alzheimer's disease (AD) is characterized by Aβ and tau lesions, and currently it is lack of ideal treatment. In recent years, using strategy based on single target, drugs designed directly for Aβ or tau failed to achieve positive outcomes, and new research ideas for the research and development of new anti-AD drugs are urgently needed. More and more evidences suggested that Aβ and tau lesions in AD are two independent pathways that affect and cause each other, and the single pathway targeting strategy may always show limited effects on the other pathway. In the previous study, our research group found that SNP-9, a polypeptide with unique mechanisms, can inhibit Aβ and tau lesions and exhibit anti-AD effects through two independent pathways. It has shown significant effects in a variety of AD animal models. At present, the mechanisms underlying the effects of SNP-9 against Aβ lesion have been elucidated, and it has been found that CacyBP may play a key role in the effects of SNP-9 against tau lesion. However, the specific mechanisms remain to be elucidated. In this project we will first confirm the role of CacyBP in mediating anti-AD action of SNP-9, and analyze the mode of interaction between SNP-9 and CacyBP. Furthermore, we will analyze the molecular pathways underlying the effects of SNP-9 on tau lesion in AD through targeted regulation of CacyBP. The aims of this project are to elucidate the anti-AD mechanisms of SNP-9, to provide the candidate molecule for the research and development of new anti-AD drugs, and to provide new research ideas for potential targets in AD.