加减薯蓣丸调节转录因子EB介导的自噬溶酶体通路改善APP/PS1小鼠学习记忆能力研究
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中国中医科学院中医基础理论研究所自主选题“院所协同创新科研专项基金”(YZ-1852);湖北省自然科学基金重点项目(2015CFA089);湖北中医药大学研究生创新能力提升项目


Modified Dioscorea opposita Thunb. Pill Improves the Learning and Memory Abilities of APP/PS1 Mice by Regulating the Transcription Factor EB-mediated Autophagy-Lysosomal Pathway
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    摘要:

    目的 研究加减薯蓣丸对APP/PS1模型小鼠的保护作用及可能机制。方法 选取20只5月龄APP/PS1小鼠分为模型组、中药组,每组10只,另设同窝野生型小鼠10只为对照组,中药组给予加减薯蓣丸每日14 g/kg干预4周,其余给予等容积生理盐水灌胃,Morris水迷宫检测学习记忆能力,ELISA检测海马组织β淀粉样蛋白42(amyloid-β42,Aβ42)水平,Western blot检测海马区微管相关蛋白3(microtubule-associated light chain3,LC3)-Ⅱ/LC3-Ⅰ、P62蛋白、组织蛋白酶B(cathepsin B,CTSB)、溶酶体膜相关蛋白1(lysosomal-associated membrane proteins 1,LAMP1)、总转录因子EB(transcription factor EB,TFEB)、核内TFEB蛋白水平。结果 与对照组相比,模型组小鼠逃避潜伏期延长(P<0.05),穿越平台次数及在原平台象限停留时间占比均显著减少(P<0.05);与模型组相比,中药组小鼠逃避潜伏期缩短(P<0.05),穿越平台次数及在原平台象限停留时间占比明显增多(P<0.05)。与对照组相比,模型组小鼠海马组织中Aβ42含量显著升高,LC3-Ⅱ/LC3-Ⅰ比值显著升高,P62蛋白、细胞核内TFEB和总TFEB表达水平均显著上调(P<0.05),LAMP1、CTSB蛋白表达水平均显著下调(P<0.05);与模型组比较,中药组小鼠海马组织中Aβ42含量显著降低(P<0.05),LAMP1、CTSB、细胞核内TFEB表达水平均显著上调(P<0.05),P62蛋白表达水平显著下调(P<0.05),LC3-Ⅱ/LC3-Ⅰ比值、总TFEB水平无明显变化(P>0.05)。结论 加减薯蓣丸通过促进TFEB核转移增强自噬溶酶体途径,减少海马区Aβ42水平,改善APP/PS1模型小鼠学习记忆能力。

    Abstract:

    Objective To investigate the protective effect of Modified Dioscorea opposita Thunb. Pill on APP/PS1 mice and the possible mechanism. Methods A total of 20 APP/PS1 mice, aged 5 months, were divided into model group and traditional Chinese medicine (TCM) group, with 10 mice in each group, and 10 wild-type littermates were selected as control group. The mice in the TCM group were given the intervention with Modified Dioscorea opposita Thunb. Pill at a dose of 14 g/(kg·d) for 4 weeks, and those in the other two groups were given an equal volume of normal saline. Morris water maze was used to evaluate the learning and memory abilities; ELISA was used to measure the level of amyloid-β42 (Aβ42) in the hippocampus; Western blot was used to measure the protein expression of microtubule-associated light chain 3 (LC3)-Ⅱ/LC3-Ⅰ, sequestosome 1 (P62), cathepsin B (CTSB), lysosomal-associated membrane proteins 1 (LAMP1), total transcription factor EB (TFEB), and nuclear TFEB in the hippocampus. Results Compared with the control group, the model group had a significant increase in escape latency (P<0.05) and significant reductions in the number of platform crossings and the percentage of time spent in the original quadrant (P<0.05). Compared with the model group, the TCM group had a significant reduction in escape latency (P<0.05) and significant increases in the number of platform crossings and the percentage of time spent in the original quadrant (P<0.05). Compared with the control group, the model group had significant increases in Aβ42 level in the hippocampus, LC3-Ⅱ/LC3-Ⅰ ratio, and protein expression of P62, nuclear TFEB, and total TFEB (P<0.05), as well as significant reductions in the protein expression of LAMP1 and CTSB (P<0.05). Compared with the model group, the TCM group had a significant reduction in Aβ42 level in the hippocampus (P<0.05), significant increases in the protein expression of LAMP1, CTSB, and nuclear TFEB (P<0.05), and a significant reduction in the protein expression of P62 (P<0.05), with no significant changes in LC3-Ⅱ/LC3-Ⅰ ratio and total TFEB (P>0.05). Conclusion Modified Dioscorea opposita Thunb. Pill can improve the learning and memory abilities of APP/PS1 mice by promoting TFEB nuclear transfer, enhancing the autophagy-lysosomal pathway, and reducing the level of Aβ42 in the hippocampus.

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邱 静,鄢文静,张雨婷,谭子虎,杨 琼.加减薯蓣丸调节转录因子EB介导的自噬溶酶体通路改善APP/PS1小鼠学习记忆能力研究[J].安徽中医药大学学报,2020,39(1):60-64

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  • 在线发布日期: 2020-01-17