马钱苷通过抑制蛋白磷酸酶2A催化亚基C磷酸化降低tau蛋白过度磷酸化

doi:10.3969/j.issn.1006-7795.2016.06.014

首都医科大学学报 ›› 2016, Vol. 37 ›› Issue (6): 789-793.doi: 10.3969/j.issn.1006-7795.2016.06.014

• 神经系统疾病的基础研究 • 上一篇下一篇

马钱苷通过抑制蛋白磷酸酶2A催化亚基C磷酸化降低tau蛋白过度磷酸化

杨翠翠, 李林, 张丽, 李雅莉, 张兰

首都医科大学宣武医院药物研究室北京市神经药物工程研究中心北京脑重大疾病研究院神经变性病教育部重点实验室, 北京 100053

收稿日期:2016-10-14 出版日期:2016-12-21 发布日期:2016-12-16
通讯作者: 张兰 E-mail:lanizhg@126.com
基金资助:
国家自然科学基金项目（81473373），北京市自然科学基金项目（7164315），北京市卫生系统高层次卫生技术人才（2014-2-014），北京市新世纪百千万人才工程（008-0014）

Loganin attenuates tau hyper-phosphorylation by inhibiting phosphorylation of PP2A catalytic subunit C

Yang Cuicui, Li Lin, Zhang Li, Li Yali, Zhang Lan

Department of Pharmacology, Xuanwu Hospital, Capital Medical University, Beijing Engineering Research Center for Nerve System Drugs, Beijing Institute for Brain Disorders, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing 100053, China

Received:2016-10-14 Online:2016-12-21 Published:2016-12-16
Supported by:
This study was supported by National Natural Science Foundation of China (81473373), Natural Science Foundation of Beijing (7164315), Beijing Health and Technical Personal of High-Level Plan (2014-2-014), Beijing New Century Talented Person Project(008-0014).

摘要/Abstract

摘要： 目的探讨马钱苷对tau蛋白过度磷酸化的影响及其作用机制。方法马钱苷（500、1 000 μmol/L）与人神经母细胞瘤细胞株（SK-N-SH细胞）预孵育24 h，之后加入PI3K抑制剂Wortmannin（WT）及PKA抑制剂GF-109203X（GFX）与SK-N-SH细胞孵育3 h，采用Western blotting方法观察马钱苷对tau蛋白在Thr205、Thr217、PHF-1位点的磷酸化，GSK-3β-Ser9、GSK-3β、PP2A催化亚基C（protein phosphatase 2A catalytic subunit C，PP2Ac）磷酸化/甲基化及PP2Ac的表达。结果 WT/GFX明显抑制p-GSK-3β-ser9的表达，引起GSK-3β活性增高，从而导致tau蛋白Thr205、Thr217、PHF-1位点高度磷酸化。马钱苷能够明显抑制模型细胞tau蛋白在Thr205、Thr217、PHF-1位点的过度磷酸化，但是不能增高p-GSK-3β-ser9的表达，提示马钱苷抑制tau蛋白磷酸化的作用不是通过影响GSK-3β通路实现的。但是实验显示马钱苷能够抑制PP2A催化亚基C Tyr307位点的磷酸化，但对Leu309位点甲基化无影响。结论马钱苷能够抑制tau蛋白过度磷酸化，机制可能与其抑制PP2A催化亚基C Tyr307位点的磷酸化，提高PP2A活性有关，与GSK-3β通路无关。

关键词: 马钱苷, tau蛋白过度磷酸化, 糖原合成酶激酶-3β, 蛋白磷酸酯酶2A, 阿尔茨海默病

Abstract: Objective To investigate the effects and mechanisms of Loganin on tau phosphorylation.Methods Human neuroblastoma SK-N-SH cells were pre-incubated with Loganin (500 μmol/L,1 000 μmol/L, respectively) for 24 h, and then exposed to 10 μmol/L WT and 10 μmol/L GFX for 3 h after washing out Loganin. Western blotting was used to measure the phosphorylation level of tau protein at Thr205, Thr217, PHF-1 sites, glycogen synthase kinase 3β (GSK-3β), protein phosphatase 2A catalytic subunit C (PP2Ac) and the related proteins in the signaling pathway. Results WT/GFX inhibited the phosphorylation of GSK-3β-ser9, increased tau phosphorylation in SK-N-SH cells. Pre-incubation with Loganin significantly attenuated hyperphosphorylation of tau at Thr205,Thr217,PHF-1 sites in the model cells. Loganin did not reverse the decrease in p-GSK3β-ser9 induced by WT/GFX, suggesting that the effect of Loganin's inhibiting tau hyperphosphorylation may be independent of GSK-3β pathway. However, Loganin reduced the phosphorylation of PP2Ac at Tyr307, but not demethylation of PP2Ac at Leu309 in the WT/GFX-treated cells. Conclusion Loganin attenuated the hyperphosphorylation of tau at multiple sites by reducing the phosphorylation of PP2Ac in Alzheimer's disease-like cell model, independent of regulating GSK-3β.

Key words: Loganin, tau hyperphosphorylation, glycogen synthase kinase-3β, protein phosphatase 2A, Alzheimer's disease

中图分类号:

R749.1

杨翠翠, 李林, 张丽, 李雅莉, 张兰. 马钱苷通过抑制蛋白磷酸酶2A催化亚基C磷酸化降低tau蛋白过度磷酸化[J]. 首都医科大学学报, 2016, 37(6): 789-793.

Yang Cuicui, Li Lin, Zhang Li, Li Yali, Zhang Lan. Loganin attenuates tau hyper-phosphorylation by inhibiting phosphorylation of PP2A catalytic subunit C[J]. Journal of Capital Medical University, 2016, 37(6): 789-793.

参考文献

[1] Nussbaum R L, Ellis C E. Alzheimer's disease and Parkinson's disease[J]. N Engl J Med, 2003,348(14):1356-1364.
[2] Sankaranarayanan S, Barten D M, Vana L, et al. Passive immunization with phospho-tau antibodies reduces tau pathology and functional deficits in two distinct mouse tauopathy models[J].PLoS One, 2015, 10(5):e0125614.
[3] Chang E, Congdon E E, Honson N S, et al. Structure-activity relationship of cyanine tau aggregation inhibitors[J]. J Med Chem, 2009, 52(11): 3539-3547.
[4] Miller E C, Teravskis P J, Dummer B W, et al. Tau phosphorylation and tau mislocalization mediate soluble Aβoligomer-induced AMPA glutamate receptor signaling deficits[J]. Eur J Neurosci,2014,39(7):1214-1224.
[5] Bennecib M, Gong C X, Grundke-Iqbal I, et al. Inhibition of PP-2AupregulatesCaMKⅡ in rat forebrain and induces hyperphosphorylation of tau at Ser262/356[J]. FEBS Lett, 2001,490(1-2): 15-22.
[6] Pei J J, Gong C X, An W L, et al. Okadaic-acid-induced inhibition of protein phosphatase 2A produces activation of mitogen-activated protein kinases ERK1/2, MEK1/2, and p70S6, similar to that in Alzheimer's disease[J]. Am J Pathol, 2003, 163(3):845-858.
[7] Liu S J, Zhang J Y, Li H L, et al. Tau becomes a more favorable substrate for GSK-3 when it is prephosphorylated by PKA in rat brain[J]. J Biol Chem, 2004, 279(48):50078-50088.
[8] Wang J Z, Gong C X, Zaidi T, et al. Dephos-phorylation of Alzheimer paired helical ? laments by protein phosphatase-2A and -2B[J]. J Biol Chem,1995, 270(9): 4854-4860.
[9] Liu F, Grundke-Iqbal I, Iqbal K, et al. Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation[J]. Eur J Neurosci, 2005, 22(8):1942-1950.
[10] 魏群, 于大禹, 吴和珍.阿尔茨海默病与tau蛋白的磷酸化及去磷酸化[J]. 中国航天医药杂志,2004, 6(2): 1-5.
[11] Bakota L, Brandt R. Tau biology and tau-directed therapies for Alzheimer's disease[J]. Drugs, 2016, 76(3):301-313.
[12] Qian W, Shi J, Yin X, et al. PP2A regulates tau phosphorylation directly and also indirectly via activating GSK-3beta[J]. J Alzheimers Dis, 2010, 19(4): 1221-1229.
[13] 刘迎新, 邹大威,耿建国,等. 糖肾宁对自发性2型糖尿病KK-Ay小鼠肾组织HGF表达的影响[J]. 首都医科大学学报,2015,36(5):747-750.
[14] Saltiel A R, Kahn C R. Insulin signalling and the regulation of glucose and lipid metabolism[J]. Nature, 2001,414(6865):799-806.
[15] Lizcano J M, Alessi D R. The insulin signallingpathway[J]. Curr Biol,2002, 12(7): R236-238.
[16] Elliott E, Atlas R, Lange A, et al. Brain-derived neurotrophic factor induces a rapid dephosphorylation of tau protein through a PI-3Kinase signallingmechanism[J]. Eur J Neurosci, 2005, 22(5):1081-1089.
[17] Xu G G, Deng Y Q, Liu S J,et al. Prolonged Alzheimer-like tau hyperphosphorylation induced by simultaneous inhibition of phosphoinositol-3 kinase and protein kinase C in N2acells[J]. Acta Biochim Biophys Sin(Shanghai),2005,37(5):349-354.
[18] Wang Y X, Yang R Y, Gu J L, et al. Cross talk between PI3K-AKT-GSK-3β and PP2A pathways determines tau hyperphosphorylation[J]. Neurobiol Aging, 2015, 36(1): 188-200.
[19] Chen J, Martin B L, Brautigan D L, et al. Regulation of protein serine-threonine phosphatase type-2A by tyrosine phosphorylation[J]. Science,1992, 257(5074):1261-1264.
[20] Bryant J C, Westphal R S, Wadzinski B E. Methylated C-terminal leucine residue of PP2A catalytic subunit is important for binding of regulatory Balpha subunit[J]. Biochem J, 1999, 339(Pt2): 241-246.
[21] Yao X Q, Li X C, Zhang X X, et al. Glycogen synthase kinase-3beta regulates leucine-309 demethylation of protein phosphatase-2A via PPMT1 and PME-1[J]. FEBS Lett, 2012, 586(16): 2522-2528.

马钱苷通过抑制蛋白磷酸酶2A催化亚基C磷酸化降低tau蛋白过度磷酸化

Loganin attenuates tau hyper-phosphorylation by inhibiting phosphorylation of PP2A catalytic subunit C

PDF

可视化

被引次数

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

本文评价

[1]	孟霞, 李梦, 王晶晶, 张静, 陈柏安, 卢静. 5xFAD转基因小鼠与阿尔茨海默病患者大脑中β-淀粉样蛋白特征的异同[J]. 首都医科大学学报, 2022, 43(1): 106-112.
[2]	马登磊, 李延峥, 祝艳秋, 李林, 张兰. 山茱萸环烯醚萜苷对快速老化小鼠行为学及病理学改变的影响[J]. 首都医科大学学报, 2021, 42(5): 754-760.
[3]	詹敏敏, 马慧萱, 康雪纯, 鲁新亮, 宫淑婷, 邹琦, 吕继辉, 周爱红, 贾建平, 魏翠柏. 轻中度阿尔茨海默病患者精神行为学症状特点及关联性分析[J]. 首都医科大学学报, 2021, 42(3): 354-359.
[4]	胡月青, 吕继辉, 王嫱, 马宗娟, 李文杰, 母海燕, 李沫, 高文超, 贾东梅. 音乐疗法联合强光治疗对阿尔茨海默病患者睡眠障碍的疗效观察[J]. 首都医科大学学报, 2021, 42(3): 367-372.
[5]	郝淑文, 陈瑛, 丁晖, 赵春松, 梁阔, 薛金花, 蔡彦宁. 阿尔茨海默病、轻度认知功能障碍及主观认知下降患者血液DNA中多个基因的甲基化分析[J]. 首都医科大学学报, 2021, 42(3): 447-452.
[6]	李妍. 守护“记忆之魂”的中国痴呆临床研究引领者——贾建平教授[J]. 首都医科大学学报, 2020, 41(5): 822-827.
[7]	杨翠翠, 包训杰, 张丽, 李雅莉, 李林, 张兰. 7月龄及16月龄APP/PS1/tau三转基因小鼠脑内突触相关蛋白的变化及山茱萸环烯醚萜苷的影响[J]. 首都医科大学学报, 2020, 41(3): 391-396.
[8]	马登磊, 张旭, 张丽, 李雅莉, 张兰, 李林. 山茱萸环烯醚萜苷对创伤性脑损伤大鼠认知功能及tau蛋白磷酸化的影响[J]. 首都医科大学学报, 2020, 41(3): 397-402.
[9]	杨翠翠, 包训杰, 张丽, 李雅莉, 李林, 张兰. 山茱萸环烯醚萜苷对APP/PS1/Tau三转基因小鼠脑内病理变化的影响[J]. 首都医科大学学报, 2019, 40(4): 588-595.
[10]	唐煜, 郝单单, 秦玮婷, 文潇, 李放. 轻度阿尔茨海默病患者年龄对蒙特利尔认知评估量表基本版得分的影响[J]. 首都医科大学学报, 2019, 40(4): 652-655.
[11]	樊响, 杨延辉, 贾秀琴, 卢洁, 李坤成. 轻度认知障碍静息态功能磁共振研究低频振幅分析[J]. 首都医科大学学报, 2018, 39(2): 163-166.
[12]	金贺, 赵志炜, 王蓉. 追赶生长与阿尔茨海默病相关性[J]. 首都医科大学学报, 2017, 38(6): 831-834.
[13]	尹晓敏, 徐婷, 戴伍飞, 钱嘉逸, 陈晨, 张兰, 李林. 二苯乙烯苷对神经细胞淀粉样肽前体蛋白表达的影响及其与CREB调节相关的作用机制[J]. 首都医科大学学报, 2017, 38(6): 835-840.
[14]	李雪莲, 杨翠翠, 张兰, 石京山. 山茱萸环烯醚萜苷对蛋白磷酸酶2A催化亚基C磷酸化的调节机制[J]. 首都医科大学学报, 2016, 37(6): 777-783.
[15]	李晖, 齐志刚, 李坤成. 针灸治疗阿尔茨海默病机制研究进展[J]. 首都医科大学学报, 2015, 36(5): 809-813.