title: Stimulation of EphB2 attenuates tau phosphorylation through PI3K/Akt-mediated inactivation of glycogen synthase kinase-3β.
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.affiliation: 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.
authors.forename: Jun
authors.initials: J
authors.lastname: Jiang
authors.affiliation: 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.
authors.forename: Zhi-Hao
authors.initials: ZH
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Min
authors.initials: M
authors.lastname: Qu
authors.affiliation: 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.
authors.forename: Di
authors.initials: D
authors.lastname: Gao
authors.affiliation: 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.
authors.forename: Xiu-Ping
authors.initials: XP
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Ling-Qiang
authors.initials: LQ
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Jian-Zhi
authors.initials: JZ
authors.lastname: Wang
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D036387:Ephrin-B1 / Q000235:genetics / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D036183:Receptor, EphB2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D036387:Ephrin-B1; D011993:Recombinant Fusion Proteins; D016875:tau Proteins; D058539:Phosphatidylinositol 3-Kinase; D036183:Receptor, EphB2; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3