title: LiCl attenuates thapsigargin-induced tau hyperphosphorylation by inhibiting GSK-3β in vivo and in vitro.
abstract: Abnormal hyperphosphorylation of microtubule-associated protein tau is involved in the pathogenesis of several neurodegenerative diseases, including Alzheimer's disease (AD). Endoplasmic reticulum (ER) stress is indicated to play an important role in neurodegeneration and activation of glycogen synthase kinase-3β (GSK-3β), an integral kinase in tau phosphorylation. To explore the effect of ER stress on tau phosphorylation, we treated cultured cells (HEK293 and SH-SY5Y cells) and rat brain with thapsigargin, an ER stress inducer. We found that the phosphorylation level of tau was significantly increased after thapsigargin treatment. By using a cell-free reconstitution system, we also observed that co-culture of the thapsigargin-treated ER fraction from HEK293/wt (without tau) with cytoplasm prepared from HEK293/tau induced an increased tau phosphorylation. Concurrently, activation of GSK-3β as evidenced by an increased phospho-GSK-3β at Tyr-216 and decreased phospho-GSK-3β at Ser-9 both in vitro and in vivo was detected. Application of lithium chloride, a GSK-3β inhibitor, could efficiently attenuate the thapsigargin-induced tau hyperphosphorylation with suppressed activation of GSK-3β in cell cultures and rat brains. Our data provide further evidence supporting the role of ER stress in tau hyperphosphorylation and the protective role of lithium.
authors.affiliation: Department of Pathophysiology, Key Laboratory of Neurological Disease of National Education Ministry, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Zheng-Qi
authors.initials: ZQ
authors.lastname: Fu
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.forename: Jie
authors.initials: J
authors.lastname: Song
authors.forename: Qian
authors.initials: Q
authors.lastname: Jiang
authors.forename: Zan-Chao
authors.initials: ZC
authors.lastname: Lin
authors.forename: Qun
authors.initials: Q
authors.lastname: Wang
authors.forename: Ling-Qiang
authors.initials: LQ
authors.lastname: Zhu
authors.forename: Jian-Zhi
authors.initials: JZ
authors.lastname: Wang
authors.forename: Qing
authors.initials: Q
authors.lastname: Tian
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology*; D008297:Male; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019284:Thapsigargin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D016875:tau Proteins; D019284:Thapsigargin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride