title: Inhibition of glycogen synthase kinase-3 reverses tau hyperphosphorylation induced by Pin1 down-regulation.
abstract: One of the neuropathological hallmarks of Alzheimer's disease (AD) is the occurrence of neurofibrillary tangles (NFTs) that are composed of abnormally hyperphosphorylated microtubule-associated protein tau. Abnormal tau hyperphosphorylation is mainly induced due to the imbalance between protein kinases and phosphatases. In the tanglerich subregions of the hippocampus and parietal cortex in the brain of AD patients, the levels of the phosphorylationdependent protein peptidyl-prolyl cis-trans isomerase (Pin1) were found to be low. Although Pin1 can regulate tau phosphorylation, it is not clear whether the inhibition of glycogen synthase kinase 3 (GSK-3), the primary mediator of tau phosphorylation in AD, could reverse tau hyperphosphorylation induced due to the down-regulation of Pin1. We found that while suppression of Pin1, either by using its inhibitor Juglone or a shRNA plasmid against Pin1, induces tau hyperphosphorylation and GSK-3β activation both in vivo and in vitro, inhibition of GSK-3β by SB216763 or LiCl reverses tau hyperphosphorylation. Our data suggest that GSK-3β activation plays an important role in tau hyperphosphorylation induced by the down-regulation of Pin1, and the inhibition of GSK-3β might be a potential therapeutic approach for AD pathology.
authors.affiliation: Department of Pathophysiology, Key Laboratory of Neurological Diseases of Education Committee of China, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China. zhulq@mail.hust.edu.cn
authors.forename: Yan-Si
authors.initials: YS
authors.lastname: Xiong
authors.forename: Dan-Li
authors.initials: DL
authors.lastname: Wang
authors.forename: Lu
authors.initials: L
authors.lastname: Tan
authors.forename: Xiong
authors.initials: X
authors.lastname: Wang
authors.forename: Li-Ming
authors.initials: LM
authors.lastname: Chen
authors.forename: Cheng-Xin
authors.initials: CX
authors.lastname: Gong
authors.forename: Jian-Zhi
authors.initials: JZ
authors.lastname: Wang
authors.forename: Ling-Qiang
authors.initials: LQ
authors.lastname: Zhu
mesh_terms: D000818:Animals; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009285:Naphthoquinones / Q000494:pharmacology; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; C489131:Mapt protein, rat; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009285:Naphthoquinones; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; C417521:SB 216763; D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; C000606846:PIN1 protein, human; D019696:Peptidylprolyl Isomerase; D018021:Lithium Chloride; C005134:juglone