阿尔兹海默症(AD)最主要的一个病理特征是淀粉样蛋白(Aβ)异常聚集形成的老年斑块。Aβ是由β-和γ-分泌酶依次切割淀粉样前体蛋白(APP)所得的产物。诸多研究显示许多与蛋白转运相关的Rab蛋白在Aβ产生过程中发挥重要作用。本课题前期研究发现Rab21与γ-分泌酶催化亚基-早老素(PS1)存在相互作用，并影响γ-分泌酶的活性。本项目旨在研究Rab21对γ-分泌酶活性的调控机制及其作为AD治疗潜在靶点的可能性。首先在鼠脑中进一步确认Rab21和PS1相互作用；其次在细胞水平探讨Rab21对γ-分泌酶蛋白水平、活性和细胞内转运的影响，以及Rab21是否通过调控γ-分泌酶对APP水解过程产生作用；最后在AD模型鼠中，研究Rab21对AD模型鼠认知能力及Aβ相关病理改变的影响，进一步阐明Rab21在AD发病病程中的作用，为细胞内转运过程对AD病理的调控机制提供实验依据，为AD治疗提供潜在作用靶点。

One of the pathological hallmarks of Alzheimer’s disease (AD) is the abnormal accumulation of β-Amyloid peptides (Aβ) in senile plaques. Aβ is a cleavage product derived from the amyloid precursor protein (APP) that is sequentially cleaved by β- and γ-secretases. Countless studies have indicated protein-trafficking associated Rab proteins play crucial roles in Aβ production. Our pre-experiments revealed that Rab21 protein can interact with Presenilin 1 (PS1), the catalytic subunit of γ-secretase, and also regulate the activity of γ-secretase. This project aims at studying the regulatory role of Rab21 protein on γ-secretase and the possibility of Rab21 as a potential therapeutic target of AD. Firstly, the interaction between Rab21 and PS1 will be further determined in mouse brain. Secondly, the role of Rab21 on the enzymatic activity and trafficking of γ-secretase, as well as whether Rab21 affect APP processing through γ-secretase, will be examined in cell line. Finally, the function of Rab21 on the cognitive ability, and the molecular mechanisms of Rab21 on the pathology of AD will be studied in AD-model mouse. These will provide experimental clues of Rab21 protein-trafficking on AD pathology, which raises the possibility of it being a potential target for AD therapeutics.