title: Bip enhanced the association of GSK-3β with tau during ER stress both in vivo and in vitro.
abstract: Hyperphosphorylated tau is the major component of intracellular neurofibrillary tangles, which is positively correlated with the cognitive decline in Alzheimer's disease (AD). The upstream factors leading to tau hyperphosphorylation are still not fully understood. Endoplasmic reticulum (ER) stress has been indicated in AD pathogenesis and the increased level of binding immunoglobulin protein (Bip), an important ER associated chaperon, is increased in AD brain. Here hyperphosphorylation of tau, activation of glycogen synthase kinase-3β (GSK-3β), and elevation of Bip were induced by ventricular infusion of ER stressors, tunicamycin (TM) and thapsigargin (TG), in rats. GSK-3β was found to be responsible for tau hyperphosphorylation induced by ER stressors both in vivo and in vitro. In addition, inhibited Akt, protein tyrosine phosphatase 1B, and activated Fyn were detected in vivo. Down-regulating Bip by tranfecting its siRNA plasmid significantly revised tau hyperphosphorylation in TG treated HEK293/tau cells, but the activation of GSK-3β was still observed. By immunoprecipitation, we found that the binding levels of Bip to tau and GSK-3β were significantly increased with the elevation of Bip in TM-treated rats. Moreover, in Bip overexpressed HEK293/tau cells, the binding levels of Bip to tau (mainly phosphorylated tau) and GSK-3β were also significantly increased. However, β-catenin, another important substrate of GSK-3β, was not found bound to the increased Bip. All these data suggest an essential role of Bip in GSK-3β dependent tau hyperphosphorylation in ER stress by promoting the binding of GSK-3β to tau.
authors.affiliation: Department of Pathology and Pathophysiology, Key Laboratory of Neurological Disease of National Education Ministry and Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Zan-Chao
authors.initials: ZC
authors.lastname: Liu
authors.forename: Zheng-Qi
authors.initials: ZQ
authors.lastname: Fu
authors.forename: Jie
authors.initials: J
authors.lastname: Song
authors.forename: Jia-Yu
authors.initials: JY
authors.lastname: Zhang
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Wei
authors.forename: Jiang
authors.initials: J
authors.lastname: Chu
authors.forename: Li
authors.initials: L
authors.lastname: Han
authors.forename: Na
authors.initials: N
authors.lastname: Qu
authors.forename: Jian-Zhi
authors.initials: JZ
authors.lastname: Wang
authors.forename: Qing
authors.initials: Q
authors.lastname: Tian
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D047468:Immunoprecipitation; D007276:Injections, Intraventricular; D008222:Lymphokines / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019284:Thapsigargin / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D014415:Tunicamycin / Q000494:pharmacology; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D008222:Lymphokines; D034741:RNA, Small Interfering; C485184:enhanced green fluorescent protein; C013059:immunoglobulin-binding factors; D016875:tau Proteins; D014415:Tunicamycin; D049452:Green Fluorescent Proteins; D019284:Thapsigargin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; C514014:Ppp2ca protein, rat; D054648:Protein Phosphatase 2