GPR50在阿尔茨海默病中的作用及机制研究

GPR50是位于X染色体上的孤独GPCR，在阿尔茨海默病（Alzheimer's Disease，AD）病人脑内发生变性的神经元上表达，说明GPR50可能在AD的病理发展中有重要作用。我们的初步研究亦发现：1）GPR50在APP/PS1小鼠皮层的蛋白淀粉斑周围表达；2）GPR50抑制Aβ产生；3）在SHSY5Y细胞上过表达GPR50可以保护细胞抵抗Aβ诱导的细胞毒性作用；4）GPR50可能参与tau磷酸化的过程。因此，本项目拟从Aβ产生、Aβ诱导的细胞毒性和神经突触毒性作用、tau磷酸化三个方面，利用细胞和小鼠模型，研究GPR50在AD的病理发展中的作用及机制，为治疗AD的药物研发，理解AD的病理发展机制提供有价值的参考数据。

G protein coupled receptors (GPCRs) play essential roles in drug development and neurodegenerative disease. GPR50,the x-lined orphan GPCR, is involved in the pathogenesis of Alzheimer's Disease(AD). Our preliminary data indicate: 1)GPR50 surrounds amyloud plaques in the cortex of APP/PS1 mice;2)GPR50 inhibits generation of Aβ possibly through binding to BACE;3) Overexpression of GPR50 in SHSY5Y cells protects cells from Aβ-induced toxicity;4)GPR50 may be involved in phosphorylation of tau. Therefore,this project is proposed to investigate the function and the mechanisms of GPR50 in generation of Aβ,Aβ-induced tocixity and tau pathology. The study will be expected to provide valuable data for target validation of AD and in understanding the pathogenesis of AD.