G蛋白偶联受体激酶5（GRK5）是典型的丝苏氨酸蛋白激酶，前期研究发现GRK5缺陷小鼠出现轴突肿胀现象并伴有行为认知障碍，与AD早期轴突损伤现象符合，但机制不明。课题组前期机制研究证实GRK5通过GSK3β调控Tau蛋白磷酸化、引发轴突转运障碍并最终对AD有贡献。另外课题组首次发现GRK5在AD中出现与年龄相关的膜质转移的新现象，并在GRK5功能性SNP位点研究中得到启示，最终提出‘AD中钙离子稳态失衡导致GRK5出现膜质转移、进而促进Tau蛋白磷酸化、最终影响轴突功能’的科学假设，本课题拟通过GRK5敲除小鼠、GRK5KO-APP/PS1杂交转基因小鼠作为动物模型验证此假说，研究结果将首次验证Ca2+/CaM-GRK5-GSK3β-Tau-AD的全新致病通路，为其作为AD的潜在靶点提供新机制和支持，也将AD的Ca离子内稳态失衡学说与Tau蛋白学说通过GRK5联系起来，丰富AD的发病机制。

G protein-coupled receptor kinase 5 (GRK5) is a typical silk threonine protein kinase. Previous research found that GRK5-deficient mice developed axonal swelling and behavioral cognitive impairment,which is consistent with the phenomenon of axonal injury in early onset of AD, but the mechanism is unknown. The preliminary results of our group found that GRK5 could regulate the phosphorylation of Tau protein through influencing the GSK3β, then trigger axonal transport disorders and ultimately contributed to AD. In addition,for the first time our group found a new phenomenon that GRK5 show the age-related membranous metastasis in AD mouse model, as well as the study on GRK5 functional SNP loci, we proposed that the steady-state imbalance of Ca ion in AD lead to the occurrence of membrane metastasis of GRK5, and thus promote the phosphorylation of Tau protein, and ultimately affect the function of axon. In the present study, we will verify our scientific hypothesis by GRK5 knockout mice, GRK5KO-APP/PS1 hybrid transgenic mice and the results will for the first time, validate the new pathogenesis of Ca2+/CaM-GRK5-GSK3β-Tau-AD, which will provide the new mechanism and the support for the potential new target of AD, and it will also associate the steady-state imbalance in calcium ion theory of AD with Tau protein theory of AD through GRK5, enrich the pathogenesis of AD.