XP2基因是本课题组在前期工作中发现的家族性阿尔茨海默病（Alzheimer’s disease, AD）新的候选基因，该基因编码蛋白为金属蛋白酶，功能尚不清楚，与其具有60%同源性的另一基因XP1已在功能上证实与AD发病相关，且参与了Aβ的降解通路。前期工作中我们已证实该蛋白在小鼠海马区高表达；功能预测提示在家系内发现的错义突变具有致病性；在AD细胞模型中过表达突变型XP2时Aβ42水平较野生型明显增高，提示XP2蛋白可能参与了AD的致病过程。本课题拟在此基础上，在细胞水平研究XP2基因突变对蛋白稳定性、酶活性、亚细胞定位、APP剪切、Aβ降解及细胞凋亡等的影响；同时采用慢病毒脑定位注射策略，在体分析XP2基因RNAi、野生型及突变型XP2蛋白对Aβ生成和降解及对APP23转基因小鼠病理及行为学的影响，明确XP2蛋白在AD发病过程中的可能作用，为揭示AD致病机制提供新的线索。

XP2 was a novel candidate gene of autosomal dominant inherited familial Alzheimer’s disease (AD) through exome sequencing analysis in our previous work. XP2 encoding protein belongs to the metalloprotease family. Its exact function remains unknown, however, the XP1 protein, which sharing as much as 60% homologous with XP2, has already been proved to participant in the degradation of Aβ42. Furthermore, we found that XP2 gene was highly expressed in hippocampus compared with other brain regions; the mutant residue was predicted to have functional impact by SIFT, Polyphen2 and MutationTaster. Moreover, overexpression of XP2-RNNC led to a higher Aβ42 level compared with that of wild-type XP2 in APPsw cell model. Taken together, these results suggest that XP2 has important physiological function and may play an important role in the pathogenesis of AD. In this research, we intend to clarify whether the mutants of XP2 impact its expression, stabilization, enzymatic activity, subcellular location, APP processing, Aβ degradation or cell apoptosis in cell models. In the meanwhile, brain stereotactic injection strategy will be performed to observe the behavior and histopathology alterations of APP23 transgenic mice after injecting lentivirus contained either XP2 RNAi, XP2 wild-type rescue or XP2 mutant rescue vectors into their hippocampus regions. All these might help us to understand the physiological function of XP2 and reveal its role in AD pathology, and provide new clues of pathogenesis of AD.