摘要
目的研究雷帕霉素是否可以通过抑制mTOR活性降低铝暴露引起的p-tau蛋白的沉积。方法24只SD大鼠随机分为四组:对照组、低剂量麦芽酚铝组、中剂量麦芽酚铝组和高剂量麦芽酚铝组。Morris水迷宫检测大鼠的学习记忆能力;Western blot检测海马组织中p-tau蛋白、p-mTOR和PSD95的变化情况;PC12细胞分为对照组、铝处理组、铝+溶剂对照组、铝+雷帕霉素100 nmol组、铝+雷帕霉素300 nmol组和铝+雷帕霉素500 nmol组,Western blot检测蛋白变化情况。12只大鼠分为铝处理组和铝+雷帕霉素组,Morris水迷宫检测大鼠的学习记忆能力;Western blot检测海马组织中p-tau蛋白、p-mTOR和PSD95的变化情况。结果水迷宫实验中,铝处理组大鼠的逃避潜伏期均比对照组延长,中、高剂量麦芽酚铝组逃避潜伏期明显低于对照组((35.24±4.78)、(25.92±8.80)vs(20.32±6.04),P<0.001);铝处理组大鼠的目标象限停留时间和穿越平台次数均随着铝剂量的升高而减少(P<0.05)。与对照组比较,铝处理组大鼠的海马组织中,p-mTOR/mTOR和p-tau/tau的水平均明显增高(P<0.05);PSD95蛋白明显降低(P<0.05)。在PC12细胞中,与单独铝处理组相比,雷帕霉素干预组的p-mTOR/mTOR和p-tau/tau的表达均有所减少,尤其在雷帕霉素300 nmol和雷帕霉素500 nmol干预组中,p-tau可恢复至正常对照组水平,PSD95也明显回升(P<0.05)。与单独铝处理组大鼠比较,雷帕霉素干预组的大鼠学习记忆能力明显改善,同时海马组织中p-mTOR/mTOR和p-tau/tau的表达均减少,PSD95也明显回升。结论mTOR磷酸化激活参与了铝引起的p-tau蛋白过度沉积,雷帕霉素可以通过抑制mTOR的磷酸化活性降低磷酸化tau蛋白的沉积。
Objective To investigate whether rapamycin reduces deposition of p-tau protein induced by aluminum through mTOR inhibiton.Methods The study employed four groups of 24 SD rats:control,low dose aluminum maltol(10μmol/kg Al(mal)3),medium dose aluminum maltol(20μmol/kg Al(mal)3),and high dose aluminum maltol(40μmol/kg Al(mal)3),groups.The Morris water maze(MWM)test was used to assess the learning and memory abilities of rats.p-tau,p-mTOR,and PSD95 in the hippocampus were detected by Western blot.PC12 cells were divided into control,aluminum treatment,aluminum+DMSO,aluminum+100 nmol rapamycin,aluminum+300 nmol rapamycin,and aluminum+500 nmol rapamycin groups.Protein expression changes were detected by Western blot.Twelve rats were divided into Al-treated and Al+rapamycin groups,the MWM test was used to assess learning and memory abilities of rats.p-tau,p-mTOR,and PSD95 in the hippocampus were detected by Western blot.Results The MWM test showed that the escape latency time of rats in the aluminum-treated group was longer than that in the control group,and that in medium and high dose aluminum mal groups was significantly longer than that in the control group((35.24±4.78)and(25.92±8.80)vs(20.32±6.04),P<0.001).The target quadrant residence time and crossing platform times of rats in Al exposure groups were decreased with the increase in the Al exposure dose(P<0.05).Compared with the findings in the control group,in the aluminum-treated group,p-mTOR/mTOR and p-tau/tau levels in the hippocampus of rats were significantly increased(P<0.05),and PSD95 was significantly decreased(P<0.05).Compared with the findings in the group exposed to aluminum alone,in rapamycin treatment groups,p-mTOR/mTOR and p-tau/tau were decreased,especially in 300 and 500 nmol rapamycin groups,p-tau was restored to the normal level of the control group,and PSD95 was also increased significantly(P<0.05).Compared with the findings in Al-treated groups,in Al+rapamycin group,learning and memory abilities of rats were improved,p-mTOR/mTOR and p-tau/
作者
徐义荣
纪晶晶
张广衡
田晓爱
卜凡
张叶平
XU Yirong;JI Jingjing;ZHANG Guangheng;TIAN Xiaoai;BU Fan;ZHANG Yeping(Department of Pathology,Shanxi Medical University Fenyang College,Fenyang 032200,China.;Department of Pathology,Shanxi Province Fenyang Hospital,Fenyang 032200)
出处
《中国比较医学杂志》
CAS
北大核心
2023年第8期15-21,共7页
Chinese Journal of Comparative Medicine
基金
国家自然基金青年项目(81803208)
山西省高校科技创新项目(2019L0907)。
