现有的研究证据表明小胶质细胞表型的转化在阿尔茨海默病（AD）发病过程中发挥着重要的作用。申请者前期研究发现G蛋白偶联受体调节蛋白β-arrestins（包括β-arrestin1和β-arrestin2）参与胶质细胞介导的炎症过程并起着不同的作用。因此，我们推测β-arrestins可能调节小胶质细胞M1/M2表型转化，并可能是延缓AD进程的新策略。为验证该假设，本项目拟应用CRISPR/Cas9基因编辑技术和脑内注射慢病毒等技术手段及APP/PS1转基因小鼠模型，研究β-arrestin1和β-arrestin2对小胶质细胞表型变化的调节作用和分子机制以及两者可能存在的平衡调节现象并探讨β-arrestin调节的小胶质细胞表型转化在AD病理过程中的作用。预期研究结果不仅有望揭示β-arrestins神经药理作用新机制，而且为发展靶向神经炎症的抗AD药物提供新的策略。

A number of studies have demonstrated that the microglia phenotypes transition plays an important role in the pathogenesis of Alzheimer’s disease (AD). Our previous study showed thatβ-arrestin1 and β-arrestin2, G protein coupled receptors (GPCR) regulatory proteins, enhanced or inhibited the neuroinflammation in glial cells. Therefore, we assumed that β-arrestins could regulate the M1/M2 transition of microglial and might be a new target for delaying the progression of AD. The CRISPR/Cas9 genome editing technology, intracerebral administration of viral vectors and APP/PS1 transgenic mice were used to evaluate the effects and mechanism of β-arrestin1 and β-arrestin2 on microglial phenotypes and the balance between β-arrestin1 and β-arrestin2. Moreover, the roles of microglial phenotypes mediated by β-arrestins in the pathological process of AD were further investigated. These findings will demonstrate that the new mechanism of the neuropharmacological effects of β-arrestins, and offer a new therapeutic option for developing anti-AD drugs which targeted neuroinflammation.