title: Valproate reduces tau phosphorylation via cyclin-dependent kinase 5 and glycogen synthase kinase 3 signaling pathways.
abstract: Valproate (VPA) is a widely used anticonvulsant and mood-stabilizing drug. Recent studies have shown that VPA could reduce amyloid-β generation, and improve memory deficits in transgenic mouse models of Alzheimer's disease (AD). However, whether VPA affects tau phosphorylation and the underlying mechanism has not been established. Here, we showed that systemic treatment of APP and presenilin 1 double transgenic mice with VPA (50mg/kg, once a day for 12 weeks), significantly reduced the levels of tau phosphorylation at the sites of Thr205, Ser396 and Thr231. Meanwhile, VPA treatment markedly reduced the activities of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3β (GSK3β), two protein kinases involved in abnormal hyperphosphorylation of tau. In an okadaic acid-induced tau hyperphosphorylation SH-SY5Y cell model, the anti-tau-phosphorylation effect of VPA was further confirmed, accompanied by a marked decrease in the activities of CDK5 and GSK3β. Our present data suggest that the inhibitory effects of VPA on tau hyperphosphorylation might be mediated through both CDK5 and GSK3β signaling pathways.
authors: Key Laboratory of Medical Cell Biology of Ministry of Education, China Medical University, Shenyang, PR China.
authors: Jiang-Ping
authors: JP
authors: Hu
authors: Jing-Wei
authors: JW
authors: Xie
authors: Chun-Yan
authors: CY
authors: Wang
authors: Tao
authors: T
authors: Wang
authors: Xu
authors: X
authors: Wang
authors: Si-Ling
authors: SL
authors: Wang
authors: Wei-Ping
authors: WP
authors: Teng
authors: Zhan-You
authors: ZY
authors: Wang
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002154:Calpain / Q000494:pharmacology; D045744:Cell Line, Tumor; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009447:Neuroblastoma; D010766:Phosphorylation / Q000187:drug effects; D053764:Presenilin-1 / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D013912:Threonine / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D053764:Presenilin-1; D016875:tau Proteins; D013912:Threonine; D014635:Valproic Acid; D051360:Cyclin-Dependent Kinase 5; D038362:Glycogen Synthase Kinase 3; D002154:Calpain