黄芩苷通过延缓衰老和调节自噬改善Tau转基因小鼠的认知损伤
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摘要
目的:研究黄芩苷改善TauP301L(Tau)转基因小鼠认知损伤的作用以及探讨其作用机制。方法:采取腹腔注射(ip)给予Tau转基因小鼠不同剂量(25,50和100 mg·kg-1)的黄芩苷溶液,给药体积为0. 01 m L·g-1,qd,维持1个月。Tau转基因小鼠的认知能力通过Morris水迷宫实验评估。Western Blotting方法检测异常tau蛋白,自噬和老化相关指标蛋白的表达。结果:行为学实验结果显示黄芩苷可以显著提高Tau转基因小鼠的认知功能障碍(P <0. 01)。当黄芩苷的给药剂量为100 mg·kg-1时,能有效地降低Tau转基因小鼠海马和皮层中tau蛋白和磷酸化tau蛋白的含量;同时,实验结果证明黄芩苷能减轻Tau转基因小鼠海马和皮层的细胞老化水平,增加自噬的能力。结论:黄芩苷通过延缓衰老来增强自噬的能力,进而减少tau蛋白和磷酸化tau蛋白的形成,最终达到改善Tau转基因小鼠的认知损伤。该结果提示在年老机体中,通过调节自噬能力降低异常蛋白聚集将是阿尔茨海默病早期治疗的一个很好的靶点。
Objective: To investigate the effects of baicalin on the improvement of cognitive impairment in TauP301 L mutated transgenic mice,and to explore its underlying mechanisms. Methods: Tau transgenic mice were treated with baicalin of different dosages(25,50,100 mg·kg-1). Each mouse was intraperitoneal injected in a volume of 0. 1 m L per 10 g weight daily for 1 month. The cognitive function of mice was evaluated by Morris water maze. The level of abnormal tau proteins and expression of autophagy and senescence related proteins in the hippocampus and cortex of Tau transgenic mice were analyzed by using Western-Blotting. Results: Compared with the model group,baicalin significantly improved the ability of cognition dose-dependently(P < 0. 01) in Tau transgenic mice. When the dosage of baicalin is 100 mg·kg-1,the level of tau and p-tau had been decreased in the hippocampus and cortex of Tau transgenic mice. In addition,the results showed that baicalin(100 mg·kg-1)reduced the degree of senescence and improves the activity of autophagy in the hippocampus and cortex of Tau transgenic mice. Conclusion: Baicalin may significantly improve cognitive function and degradation of tau and p-tau by delaying senescence to regulate dysfunction of autophagy in the aging brain of Tau transgenic mice. The results suggest that alleviation of abnormal protein aggregation by regulating dysfunction of autophagy in aged brain tissues would be a good target for the treatment of AD in early stage.
Objective: To investigate the effects of baicalin on the improvement of cognitive impairment in TauP301 L mutated transgenic mice,and to explore its underlying mechanisms. Methods: Tau transgenic mice were treated with baicalin of different dosages(25,50,100 mg·kg-1). Each mouse was intraperitoneal injected in a volume of 0. 1 m L per 10 g weight daily for 1 month. The cognitive function of mice was evaluated by Morris water maze. The level of abnormal tau proteins and expression of autophagy and senescence related proteins in the hippocampus and cortex of Tau transgenic mice were analyzed by using Western-Blotting. Results: Compared with the model group,baicalin significantly improved the ability of cognition dose-dependently(P < 0. 01) in Tau transgenic mice. When the dosage of baicalin is 100 mg·kg-1,the level of tau and p-tau had been decreased in the hippocampus and cortex of Tau transgenic mice. In addition,the results showed that baicalin(100 mg·kg-1)reduced the degree of senescence and improves the activity of autophagy in the hippocampus and cortex of Tau transgenic mice. Conclusion: Baicalin may significantly improve cognitive function and degradation of tau and p-tau by delaying senescence to regulate dysfunction of autophagy in the aging brain of Tau transgenic mice. The results suggest that alleviation of abnormal protein aggregation by regulating dysfunction of autophagy in aged brain tissues would be a good target for the treatment of AD in early stage.
引文
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[18] LEE MJ,LEE JH,RUBINSZTEIN DC. Tau degradation:the ubiquitin-proteasome system versus the autophagy-lysosome system[J]. Prog Neurobiol,2013,105(6):49-59.
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[23] CHILDS BG,DURIK M,BAKER DJ,et al. Cellular senescence in aging and age-related disease:from mechanisms to therapy[J]. Nat Med,2015,21(12):1424-1435.
[24]张海波,林爱花,宫平,等.神经炎症对阿尔茨海默病中tau蛋白的影响[J].中国新药杂志,2018,27(19):2245-2252.
[25] SALAMA R,SADAIE M,HOARE M,et al. Cellular senescence and its effector programs[J]. Genes Dev,2014,28(2):99-114.
[2] BLOOM GS. Amyloid-beta and tau:the trigger and bullet in Alzheimer disease pathogenesis[J]. JAMA Neurol,2014,71(4):505-508.
[3] HERRUP K. The case for rejecting the amyloid cascade hypothesis[J]. Nat Neurosci,2015,18(6):794-799.
[4] BAKOTA L,BRANDT R. Tau biology and Tau-directed therapies for Alzheimer's disease[J]. Drugs,2016,76(3):301-313.
[5] DAI CL,TUNG YC,LIU F,et al. Tau passive immunization inhibits not only tau but also Abeta pathology[J]. Alzheimers Res Ther,2017,9(1):1.
[6] NEDELSKY NB,TODD PK,TAYLOR JP. Autophagy and the ubiquitin-proteasome system:collaborators in neuroprotection[J]. Biochim Biophys Acta,2008,1782(12):691-699.
[7] DI J,COHEN LS,CORBO CP,et al. Abnormal tau induces cognitive impairment through two different mechanisms:synaptic dysfunction and neuronal loss[J]. Sci Rep,2016,6(1):20833.
[8] BOCCARDI V,COMANDUCCI C,BARONI M,et al. Of energy and entropy:the ineluctable impact of aging in old age dementia[J]. Int J Mol Sci,2017,18(12):2672.
[9] MARTINEZ M,CUERVO AM. Autophagy and neurodegeneration:when the cleaning crew goes on strike[J]. Lancet Neurol,2007,6(4):352-361.
[10] SHIN SH,BAK SS,KIM MK,et al. Baicalin,a flavonoid,affects the activity of human dermal papilla cells and promotes ana-gen induction in mice[J]. N S Arch Pharmacol,2015,388(5):583-586.
[11] ZHENG WX,CAO XL,WANG F,et al. Baicalin inhibiting cerebral ischemia/hypoxia-induced neuronal apoptosis via MRTF-Amediated transactivity[J]. Eur J Pharmacol,2015,767:201-210.
[12] CHEN C,LI X,GAO P,et al. Baicalin attenuates alzheimerlike pathological changes and memory deficits induced by amyloidβ1-42 protein[J]. Metab Brain Dis,2015,30(2):537-544.
[13] ZHANG X,TANG X,LIU H,et al. Autophagy induced by baicalin involves downregulation of CD147 in SMMC-7721 cells in vitro[J]. Oncol Rep,2012,27(4):1128-1134.
[14] ZHANG JA,YIN Z,MA LW,et al. The protective effect of baicalin against UVB irradiation induced photoaging:an in vitro and in vivo study[J]. PLoS One,2014,9(6):e99703.
[15]肖弯,曹晓璐,张容,等.黄芩苷改善Aβ_(25-35)诱导的小鼠学习和记忆障碍及可能机制[J].中国药理学与毒理学杂志,2017,31(1):59-64.
[16] TOLNAY M,PROBST A. Review:tau protein pathology in Alzheimer's disease and related disorders[J]. Neuropath Appl Neuro,1999,25(3):171-187.
[17]李俊杰,文学平,徐凌云.黄芩苷新剂型及其药理学研究进展[J].中国新药杂志,2017,26(17):2046-2051.
[18] LEE MJ,LEE JH,RUBINSZTEIN DC. Tau degradation:the ubiquitin-proteasome system versus the autophagy-lysosome system[J]. Prog Neurobiol,2013,105(6):49-59.
[19] GHAVAMI S,SHOJAEI S,YEGANEH B,et al. Autophagy and apoptosis dysfunction in neurodegenerative disorders[J]. Prog Neurobiol,2014,112:24-49.
[20] LIPPAI M,LW P. The role of the selective adaptor p62 and ubiquitin-like proteins in autophagy[J]. Bio Med Res Int,2014,2014(1):832704.
[21] TANIDA I,UENO T,KOMINAMI E. LC3 and autophagy[J].Methods Mol Biol,2008,445:77-88.
[22] GURKAR AU,CHU K,RAJ L,et al. Identification of ROCK1kinase as a critical regulator of Beclin1-mediated autophagy during metabolic stress[J]. Nat Commun,2013,4:2189.
[23] CHILDS BG,DURIK M,BAKER DJ,et al. Cellular senescence in aging and age-related disease:from mechanisms to therapy[J]. Nat Med,2015,21(12):1424-1435.
[24]张海波,林爱花,宫平,等.神经炎症对阿尔茨海默病中tau蛋白的影响[J].中国新药杂志,2018,27(19):2245-2252.
[25] SALAMA R,SADAIE M,HOARE M,et al. Cellular senescence and its effector programs[J]. Genes Dev,2014,28(2):99-114.