定向优化的海南沼蛙免疫肽通过调控小胶质细胞改善阿尔茨海默病认知功能障碍及其机制研究

阿尔茨海默病(AD)发病机制复杂，现有治疗手段单一、未能延缓疾病进展，亟待理想治疗药物。如何发现AD新药是目前该领域的重要挑战。小胶质细胞过度激活在AD致病机制中发挥重要作用，我们近期研究发现定向优化的海南沼蛙GHaR和GHa11R免疫肽可明显改善H2O2造成的神经细胞损伤；显著抑制LPS诱导的BV2小胶质细胞炎症；有效改善LPS诱导的认知功能障碍小鼠的学习与认知能力，提示针对小胶质细胞的靶向治疗有望成为全新机制的抗AD候选药物。基于此，我们提出科学假说，GHaR和GHa11R可通过调控小胶质细胞改善AD的症状并延缓其发展。本项目将采用APP/PS1/Tau三转基因AD小鼠模型、APP过表达AD治疗药物细胞筛选模型、原代小胶质细胞和BV2炎症细胞模型为媒介，通过神经电生理、分子生物学等手段，从体内和体外两个层次进行研究，为GHaR和GHa11R免疫肽作为治疗AD的候选药物提供科学依据。

The pathogenesis of AD still remains unclear. Some therapeutic drugs have been currently approved for AD, all dealing with the symptoms rather than the underlying causes of the disease. This is exacerbated by the notion that we are indeed unaware of the underlying and causative disease mechanisms in AD. Screening and development of new drugs for AD have always been a big challenge in this field. Over-activated microglia are emerging as key contributors to AD pathology. Our previous study found that the optimal immune peptides GHaR and GHa11R from Hylarana guentheri could improve H2O2-induced cytotoxicity and inhibit LPS-stimulated BV2 microglia inflammation response. We also found that they could improve the learning and cognitive abilities of LPS-stimulated C57BL/6J cognitive defects mouse model. In the present study，we will explore the effects of GHaR and GHa11R on AD and its underlying mechanisms using APP/PS1/Tau triple-transgenic AD mouse model, an over expression APP model for anti-Alzheimer Disease drug screening and Aβ1-42 or LPS-induced microglia and BV2 cell model, and further investigate whether GHaR and GHa11R presents as a novel therapeutic area for the management of AD.