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17beta-estradiol attenuates glycogen synthase kinase-3beta activation and tau hyperphosphorylation in Akt-independent manner.
J Neural Transm (Vienna). 2008 Jun; 115(6):879-88.JN

Abstract

Decline of estrogen is associated with high incidence of Alzheimer's disease (AD) characterized pathologically with tau hyperphosphorylation, and glycogen synthase kinase-3beta (GSK-3beta) is a major tau kinase. However, the role of estrogen on GSK3beta-induced tau hyperphosphorylation is elusive. Here, we treated N2a cells with wortmannin (Wort) and GF-109203X (GFX) or gene transfection to activate GSK-3beta and to induce tau hyperphosphorylation and then the effects of 17beta-estradiol (betaE2) on tau phosphorylation and GSK-3beta activity were studied. We found that betaE2 could attenuate tau hyperphosphorylation at multiple AD-related sites, including Ser396/404, Thr231, Thr205, and Ser199/202, induced by Wort/GFX or transient overexpression of GSK-3beta. Simultaneously, it increased the level of Ser9-phosphorylated (inactive) GSK-3beta. To study whether the protective effect of betaE2 on GSK-3beta and tau phosphorylation involves protein kinase B (Akt), an upstream effector of GSK-3, we transiently expressed the dominant negative Akt (dnAkt) in the cells. We found that betaE2 could attenuate Wort/GFX-induced GSK-3beta activation and tau hyperphosphorylation with Akt-independent manner. It suggests that betaE2 may arrest AD-like tau hyperphosphorylation by directly targeting GSK-3beta.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Shi HR
Department of Pathophysiology, Key Laboratory of Neurological Disease of Ministry of Education and Hubei Province, Tongji Medical College, HuaZhong University of Science and Technology, Wuhan, PR China.
Zhu LQ
No affiliation info available
Wang SH
No affiliation info available
Liu XA
No affiliation info available
Tian Q
No affiliation info available
Zhang Q
No affiliation info available
Wang Q
No affiliation info available
Wang JZ
No affiliation info available

MeSH

Alzheimer DiseaseAndrostadienesAnimalsCell Line, TumorCytoprotectionEnzyme ActivationEnzyme InhibitorsEstradiolGlycogen Synthase Kinase 3Glycogen Synthase Kinase 3 betaIndolesMaleimidesMiceNeurofibrillary TanglesNeuronsNeuroprotective AgentsPhosphorylationProto-Oncogene Proteins c-aktTransfectionUp-RegulationWortmannintau Proteins

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18217188

Citation

Shi, Hai-Rong, et al. "17beta-estradiol Attenuates Glycogen Synthase Kinase-3beta Activation and Tau Hyperphosphorylation in Akt-independent Manner." Journal of Neural Transmission (Vienna, Austria : 1996), vol. 115, no. 6, 2008, pp. 879-88.
Shi HR, Zhu LQ, Wang SH, et al. 17beta-estradiol attenuates glycogen synthase kinase-3beta activation and tau hyperphosphorylation in Akt-independent manner. J Neural Transm (Vienna). 2008;115(6):879-88.
Shi, H. R., Zhu, L. Q., Wang, S. H., Liu, X. A., Tian, Q., Zhang, Q., Wang, Q., & Wang, J. Z. (2008). 17beta-estradiol attenuates glycogen synthase kinase-3beta activation and tau hyperphosphorylation in Akt-independent manner. Journal of Neural Transmission (Vienna, Austria : 1996), 115(6), 879-88. https://doi.org/10.1007/s00702-008-0021-z
Shi HR, et al. 17beta-estradiol Attenuates Glycogen Synthase Kinase-3beta Activation and Tau Hyperphosphorylation in Akt-independent Manner. J Neural Transm (Vienna). 2008;115(6):879-88. PubMed PMID: 18217188.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 17beta-estradiol attenuates glycogen synthase kinase-3beta activation and tau hyperphosphorylation in Akt-independent manner. AU - Shi,Hai-Rong, AU - Zhu,Ling-Qiang, AU - Wang,Shao-Hui, AU - Liu,Xin-An, AU - Tian,Qing, AU - Zhang,Qi, AU - Wang,Qun, AU - Wang,Jian-Zhi, Y1 - 2008/01/24/ PY - 2007/11/06/received PY - 2008/01/07/accepted PY - 2008/1/25/pubmed PY - 2008/10/4/medline PY - 2008/1/25/entrez SP - 879 EP - 88 JF - Journal of neural transmission (Vienna, Austria : 1996) JO - J Neural Transm (Vienna) VL - 115 IS - 6 N2 - Decline of estrogen is associated with high incidence of Alzheimer's disease (AD) characterized pathologically with tau hyperphosphorylation, and glycogen synthase kinase-3beta (GSK-3beta) is a major tau kinase. However, the role of estrogen on GSK3beta-induced tau hyperphosphorylation is elusive. Here, we treated N2a cells with wortmannin (Wort) and GF-109203X (GFX) or gene transfection to activate GSK-3beta and to induce tau hyperphosphorylation and then the effects of 17beta-estradiol (betaE2) on tau phosphorylation and GSK-3beta activity were studied. We found that betaE2 could attenuate tau hyperphosphorylation at multiple AD-related sites, including Ser396/404, Thr231, Thr205, and Ser199/202, induced by Wort/GFX or transient overexpression of GSK-3beta. Simultaneously, it increased the level of Ser9-phosphorylated (inactive) GSK-3beta. To study whether the protective effect of betaE2 on GSK-3beta and tau phosphorylation involves protein kinase B (Akt), an upstream effector of GSK-3, we transiently expressed the dominant negative Akt (dnAkt) in the cells. We found that betaE2 could attenuate Wort/GFX-induced GSK-3beta activation and tau hyperphosphorylation with Akt-independent manner. It suggests that betaE2 may arrest AD-like tau hyperphosphorylation by directly targeting GSK-3beta. SN - 0300-9564 UR - https://www.unboundmedicine.com/medline/citation/18217188/17beta_estradiol_attenuates_glycogen_synthase_kinase_3beta_activation_and_tau_hyperphosphorylation_in_Akt_independent_manner_ DB - PRIME DP - Unbound Medicine ER -