年龄增长对GRK5基因缺陷小鼠海马内肿胀轴突丛形成与积累的影响

Effect of aging on the changes of swollen axonal clusters in hippocampus of mice with GRK5 deficiency

目的研究G蛋白偶联受体(G protein-coupled receptors)激酶5(GPCR kinase-5,GRK5)基因缺陷和老化交互作用对阿尔茨海默病(Alzheimer’s disease,AD)早期的病理改变-海马内肿胀轴突丛(swollen axonal clusters,SACs)出现和积累的影响。方法选取5、6、7、9、12-13、18-19月龄雌性GRK5基因敲除小鼠(GRK5Knockout,GRK5KO)作为观察对象,另选取年龄匹配的雌性野生型(wild type,WT)小鼠为对照,每个年龄段GRK5KO和WT小鼠各4只。用抗人神经原纤维缠结(neurofibrillary tangles,NFTs)特异性抗体的免疫荧光染色方法观察海马内SACs的变化。结果所有小鼠随着年龄增长,海马内SACs逐渐增加;GRK5KO小鼠组海马内NFT+SACs数量较WT型小鼠组显著增加(P<0.01);双因素方差分析显示遗传性GRK5基因缺陷和老化双因素对海马内NFT+SACs的影响有显著协同效应(P<0.01)。结论在促进早期AD病理发生的过程中,GRK5缺陷和老化双因素共同加剧了雌性GRK5KO小鼠海马内SACs的形成与积累。

Objective To determine the interaction between GRK5 deficiency and aging in promoting the formation and build-up of swollen axonal clusters （SACs）, early AD-like pathologic changes, in the hippoeampus. Methods Immunofluorescent staining was used to evaluate the SACs in the hippocampus in 5-, 6-, 7-, 9-, 12 to 13-, 18 to 19-month-old female GRK5 Knockout （GRKSKO） mice and the agematched female wild-type （WT） mice （n = 4）. Results The number of SACs in all the mice, including GRKSKO and WT mice, was found to be increased gradually with age, which developed in an age-dependent manner. The number of SACs was significantly higher in GRKSKO mice than in WT mice （P〈0.01）. Two-way ANOVA revealed a significant interaction between age and GRK5 genotype （P〈0.01） in boosting the number of SACs in the aged female GRK5KO mice. Conclusion This study demonstrates that the aging factor synergistically interacts with GRK5 deficiency in promoting early AD-like pathologic changes, which leads to a worsened pathology in female GRK5KO mice.