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Stimulation of EphB2 attenuates tau phosphorylation through PI3K/Akt-mediated inactivation of glycogen synthase kinase-3β.
Sci Rep. 2015 Jun 29; 5:11765.SR

Abstract

Abnormal tau hyperphosphorylation is an early pathological marker of Alzheimer's disease (AD), however, the upstream factors that regulate tau phosphorylation are not illustrated and there is no efficient strategy to arrest tau hyperphosphorylation. Here, we find that activation of endogenous EphB2 receptor by ligand stimulation (ephrinB1/Fc) or by ectopic expression of EphB2 plus the ligand stimulation induces a remarkable tau dephosphorylation at multiple AD-associated sites in SK-N-SH cells and human embryonic kidney cells that stably express human tau (HEK293-tau). In cultured hippocampal neurons and the hippocampus of human tau transgenic mice, dephosphorylation of tau proteins was also detected by stimulation of EphB2 receptor. EphB2 activation inhibits glycogen synthase kinase-3β (GSK-3β), a crucial tau kinase, and activates phosphatidylinositol-3-kinase (PI3K)/Akt both in vitro and in vivo, whereas simultaneous inhibition of PI3K or upregulation of GSK-3β abolishes the EphB2 stimulation-induced tau dephosphorylation. Finally, we confirm that ephrinB1/Fc treatment induces tyrosine phosphorylation (activation) of EphB2, while deletion of the tyrosine kinase domain (VM) of EphB2 eliminates the receptor stimulation-induced GSK-3β inhibition and tau dephosphorylation. We conclude that activation of EphB2 receptor kinase arrests tau hyperphosphorylation through PI3K-/Akt-mediated GSK-3β inhibition. Our data provide a novel membranous target to antagonize AD-like tau pathology.

Authors+Show Affiliations

Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Neurological Diseases of Education Ministry of China, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China. Department of Oncology, The Central Hospital of Wuhan, 430014, Wuhan, China.Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Neurological Diseases of Education Ministry of China, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Neurological Diseases of Education Ministry of China, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China. Hubei Provincial Center for Disease Control and Prevention, Wuhan, P. R. China.Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Neurological Diseases of Education Ministry of China, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Neurological Diseases of Education Ministry of China, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China. Clinical Laboratory of Hangzhou Traditional Chinese Medical Hospital, Hangzhou, P. R. China.Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Neurological Diseases of Education Ministry of China, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.Department of Pathophysiology, School of Basic Medicine and the Collaborative Innovation Center for Brain Science, Key Laboratory of Neurological Diseases of Education Ministry of China, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China. Co-innovation Center of Neuroregeneration, Nantong University, Nantong, JS 226001, China.

Pub Type(s)

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

Language

eng

PubMed ID

26119563

Citation

Jiang, Jun, et al. "Stimulation of EphB2 Attenuates Tau Phosphorylation Through PI3K/Akt-mediated Inactivation of Glycogen Synthase Kinase-3β." Scientific Reports, vol. 5, 2015, p. 11765.
Jiang J, Wang ZH, Qu M, et al. Stimulation of EphB2 attenuates tau phosphorylation through PI3K/Akt-mediated inactivation of glycogen synthase kinase-3β. Sci Rep. 2015;5:11765.
Jiang, J., Wang, Z. H., Qu, M., Gao, D., Liu, X. P., Zhu, L. Q., & Wang, J. Z. (2015). Stimulation of EphB2 attenuates tau phosphorylation through PI3K/Akt-mediated inactivation of glycogen synthase kinase-3β. Scientific Reports, 5, 11765. https://doi.org/10.1038/srep11765
Jiang J, et al. Stimulation of EphB2 Attenuates Tau Phosphorylation Through PI3K/Akt-mediated Inactivation of Glycogen Synthase Kinase-3β. Sci Rep. 2015 Jun 29;5:11765. PubMed PMID: 26119563.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Stimulation of EphB2 attenuates tau phosphorylation through PI3K/Akt-mediated inactivation of glycogen synthase kinase-3β. AU - Jiang,Jun, AU - Wang,Zhi-Hao, AU - Qu,Min, AU - Gao,Di, AU - Liu,Xiu-Ping, AU - Zhu,Ling-Qiang, AU - Wang,Jian-Zhi, Y1 - 2015/06/29/ PY - 2015/03/05/received PY - 2015/05/26/accepted PY - 2015/6/30/entrez PY - 2015/6/30/pubmed PY - 2016/6/22/medline SP - 11765 EP - 11765 JF - Scientific reports JO - Sci Rep VL - 5 N2 - Abnormal tau hyperphosphorylation is an early pathological marker of Alzheimer's disease (AD), however, the upstream factors that regulate tau phosphorylation are not illustrated and there is no efficient strategy to arrest tau hyperphosphorylation. Here, we find that activation of endogenous EphB2 receptor by ligand stimulation (ephrinB1/Fc) or by ectopic expression of EphB2 plus the ligand stimulation induces a remarkable tau dephosphorylation at multiple AD-associated sites in SK-N-SH cells and human embryonic kidney cells that stably express human tau (HEK293-tau). In cultured hippocampal neurons and the hippocampus of human tau transgenic mice, dephosphorylation of tau proteins was also detected by stimulation of EphB2 receptor. EphB2 activation inhibits glycogen synthase kinase-3β (GSK-3β), a crucial tau kinase, and activates phosphatidylinositol-3-kinase (PI3K)/Akt both in vitro and in vivo, whereas simultaneous inhibition of PI3K or upregulation of GSK-3β abolishes the EphB2 stimulation-induced tau dephosphorylation. Finally, we confirm that ephrinB1/Fc treatment induces tyrosine phosphorylation (activation) of EphB2, while deletion of the tyrosine kinase domain (VM) of EphB2 eliminates the receptor stimulation-induced GSK-3β inhibition and tau dephosphorylation. We conclude that activation of EphB2 receptor kinase arrests tau hyperphosphorylation through PI3K-/Akt-mediated GSK-3β inhibition. Our data provide a novel membranous target to antagonize AD-like tau pathology. SN - 2045-2322 UR - https://www.unboundmedicine.com/medline/citation/26119563/Stimulation_of_EphB2_attenuates_tau_phosphorylation_through_PI3K/Akt_mediated_inactivation_of_glycogen_synthase_kinase_3β_ L2 - http://dx.doi.org/10.1038/srep11765 DB - PRIME DP - Unbound Medicine ER -