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Cornel Iridoid Glycoside Inhibits Tau Hyperphosphorylation via Regulating Cross-Talk Between GSK-3 beta and PP2A Signaling

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收录情况： ◇ SCIE

作者：
Yang, Cuicui[1,2,3,4] * ; Li, Xuelian[5] ; Gao, Wenbin[5] ; Wang, Qi[5] ; Zhang, Li[1,2,3,4] ; Li, Yali[2,3,4] ; Li, Lin[1,2,3,4] ; Zhang, Lan[1,2,3,4] ;
机构： [1]Department of Pharmacy, Xuanwu Hospital of Capital Medical University, Beijing, China, [2]Beijing Institute for Brain Disorders, Beijing, China, [3]Beijing Engineering Research Center for Nerve System Drugs, Beijing, China, [4]Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing, China, [5]Institute of Clinical Pharmacology, Guangzhou University of Chinese Medicine, Guangzhou, China
出处：
DOI： 10.3389/fphar.2018.00682
ISSN：

关键词： cornet iridoid glycoside Alzheimer's disease tau phosphorylation protein phosphates 2A glycogen synthase kinase-3 beta protein phosphatase methylesterase-1

摘要：
Neurofibrillary pathology contributes to neuronal dysfunction and correlates with the clinical progression of Alzheimer's disease (AD). Tau phosphorylation is mainly regulated by a balance of glycogen synthase kinase-3 beta (GSK-3 beta) and protein phosphatase 2A (PP2A) activities. Cornel iridoid glycoside (CIG) is a main component extracted from Comus officinalis. The purpose of this study was to investigate the effects of CIG on GSK-3 beta and PP2A, thus to explore the mechanisms of CIG to inhibit tau hyperphosphorylation. The rat model of tau hyperphosphorylation was established by intraventricular injection of wortmannin and GF-109203X (GFX) to activate GSK-3 beta. The results showed that intragastrical administration of CIG inhibited tau hyperphosphorylation in the brain of rats induced by wortmannin/GFX. The results in vivo and in vitro exhibited that CIG inhibited tau hyperphosphorylation and GSK-3 beta overactivation. In the mechanism of action, CIG's attenuating GSK-3 beta activity was found to be dependent on PI3K/AKT signaling pathway. PP2A catalytic C subunit (PP2Ac) siRNA abrogated the effect of CIG on PI3K/AKT/GSK-3 beta. Additionally and crucially, we also found that CIG inhibited the demethylation of PP2Ac at Leu309 in vivo and in vitro. It enhanced PP2A activity, decreased tau hyperphosphorylation, and protected cell morphology in okadaic acid (OA)-induced cell model in vitro. PP2Ac siRNA abated the inhibitory effect of CIG on tau hyperphosphorylation. Moreover, CIG inhibited protein phosphatase methylesterase-1 (PME-1) and demethylation of PP2Ac, enhanced PP2A activity, and decreased tau hyperphosphorylation in PME-1-transfectd cells. Taken together, CIG inhibited GSK-3 beta activity via promoting PI3K/AKT and PP2A signaling pathways. In addition, CIG also elevated PP2A activity via inhibiting PME-1-induced PP2Ac demethylation to inhibit GSK-3 beta activity, thus regulated the cross-talk between GSK-3 beta and PP2A signaling and consequently inhibited tau hyperphosphorylation. These results suggest that CIG may be a promising agent for AD therapy.

基金：
National Natural Science Foundation of China [81473373, 81703729, 81673406]; National Science and Technology Major Project of China [2015ZX09101-016]; Beijing Natural Science Foundation of China [7164315]; Beijing New Medical Discipline Grant [XK100270569]; Beijing High-level Health and Technical Personal Plan [2011-1-7, 2014-2-014]
语种：
外文
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PubmedID：
中科院(CAS)分区：
出版当年[2017]版：
大类 | 2 区 医学
小类 | 2 区 药学
最新[2023]版：
大类 | 2 区 医学
小类 | 2 区 药学
JCR分区：
出版当年[2016]版：
Q1 PHARMACOLOGY & PHARMACY
最新[2023]版：
Q1 PHARMACOLOGY & PHARMACY

影响因子： 最新[2023版] 最新五年平均 出版当年[2016版] 出版当年五年平均 出版前一年[2015版] 出版后一年[2017版]

第一作者：
第一作者机构： [1]Department of Pharmacy, Xuanwu Hospital of Capital Medical University, Beijing, China, [2]Beijing Institute for Brain Disorders, Beijing, China, [3]Beijing Engineering Research Center for Nerve System Drugs, Beijing, China, [4]Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing, China,
通讯作者：
通讯机构： [1]Department of Pharmacy, Xuanwu Hospital of Capital Medical University, Beijing, China, [2]Beijing Institute for Brain Disorders, Beijing, China, [3]Beijing Engineering Research Center for Nerve System Drugs, Beijing, China, [4]Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing, China,
推荐引用方式(GB/T 7714)：
Yang Cuicui,Li Xuelian,Gao Wenbin,et al.Cornel Iridoid Glycoside Inhibits Tau Hyperphosphorylation via Regulating Cross-Talk Between GSK-3 beta and PP2A Signaling[J].FRONTIERS IN PHARMACOLOGY.2018,9(JUN):682.doi:10.3389/fphar.2018.00682.
APA：
Yang, Cuicui,Li, Xuelian,Gao, Wenbin,Wang, Qi,Zhang, Li...&Zhang, Lan.(2018).Cornel Iridoid Glycoside Inhibits Tau Hyperphosphorylation via Regulating Cross-Talk Between GSK-3 beta and PP2A Signaling.FRONTIERS IN PHARMACOLOGY,9,(JUN)
MLA：
Yang, Cuicui,et al."Cornel Iridoid Glycoside Inhibits Tau Hyperphosphorylation via Regulating Cross-Talk Between GSK-3 beta and PP2A Signaling".FRONTIERS IN PHARMACOLOGY 9..JUN(2018):682

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