title: TPPU protects tau from H2O2-induced hyperphosphorylation in HEK293/tau cells by regulating PI3K/AKT/GSK-3β pathway.
abstract: Neurofibrillary pathology of abnormally hyperphosphorylated tau is a hallmark of Alzheimer's disease (AD) and other tauopathies. Phosphatidylinositol 3-kinase (PI3K)/Akt/glycogen synthase kinase-3 beta (GSK-3β) signaling pathway is pivotal for tau phosphorylation. Inhibition of soluble epoxide hydrolase (sEH) metabolism has been shown to effectively increase the accumulation of epoxyeicosatrienoic acids (EETs), which are cytochrome P450 metabolites of arachidonic acid and have been demonstrated to have neuroprotective effects. However, little is known about the role of sEH in tau phosphorylation. The present study investigated the role of a sEH inhibitor, 1-(1-propanoylpiperidin-4-yl)-3-[4-(trifluoromethoxy)phenyl] urea (TPPU), on H2O2-induced tau phosphorylation and the underlying signaling pathway in human embryonic kidney 293 (HEK293)/Tau cells. We found that the cell viability was increased after TPPU treatment compared to control in oxidative stress. Western blotting and immunofluorescence results showed that the levels of phosphorylated tau at Thr231 and Ser396 sites were increased in H2O2-treated cells but dropped to normal levels after TPPU administration. H2O2induced an obvious decreased phosphorylation of GSK-3β at Ser9, an inactive form of GSK-3β, while there were no changes of phosphorylation of GSK-3β at Tyr216. TPPU pretreatment maintained GSK-3β Ser 9 phosphorylation. Moreover, Western blotting results showed that TPPU upregulated the expression of p-Akt. The protective effects of TPPU were found to be inhibited by wortmannin (WT, a specific PI3K inhibitor). In conclusion, these results suggested that the protective effect of TPPU on H2O2-induced oxidative stress is associated with PI3K/Akt/GSK-3β pathway.
authors.affiliation: Department of Neurology, Tongji Hospital, Tongji Medicine College, Huazhong University of Science and Technology, Wuhan, 430030, China.|Department of Neurology, Shihezi University, Shihezi, 832008, China.
authors.forename: En-Sheng
authors.initials: ES
authors.lastname: Yao
authors.affiliation: Department of Geriatrics, The First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, 832008, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Neurology, Tongji Hospital, Tongji Medicine College, Huazhong University of Science and Technology, Wuhan, 430030, China. liu_xingh@126.com.
authors.forename: Xing-Hua
authors.initials: XH
authors.lastname: Liu
authors.affiliation: Department of Neurology, Tongji Hospital, Tongji Medicine College, Huazhong University of Science and Technology, Wuhan, 430030, China.
authors.forename: Ming-Huan
authors.initials: MH
authors.lastname: Wang
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D018384:Oxidative Stress; D010671:Phenylurea Compounds / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C581572:1-trifluoromethoxyphenyl-3-(1-propionylpiperidine-4-yl)urea; D004791:Enzyme Inhibitors; D010671:Phenylurea Compounds; D010880:Piperidines; D016875:tau Proteins; D006861:Hydrogen Peroxide; D019869:Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt
keywords: Alzheimer’s disease; GSK-3β; TPPU; tau