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TPPU protects tau from H2O2-induced hyperphosphorylation in HEK293/tau cells by regulating PI3K/AKT/GSK-3β pathway

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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. H2O2 induced 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.

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Authors and Affiliations

  1. Department of Neurology, Tongji Hospital, Tongji Medicine College, Huazhong University of Science and Technology, Wuhan, 430030, China

    En-sheng Yao  (姚恩生), Xing-hua Liu  (刘幸华) & Ming-huan Wang  (汪明欢)

  2. Department of Neurology, Shihezi University, Shihezi, 832008, China

    En-sheng Yao  (姚恩生)

  3. Department of Geriatrics, The First Affiliated Hospital, School of Medicine, Shihezi University, Shihezi, 832008, China

    Yan Tang  (唐 燕)

Authors
  1. En-sheng Yao  (姚恩生)
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  2. Yan Tang  (唐 燕)
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  3. Xing-hua Liu  (刘幸华)
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  4. Ming-huan Wang  (汪明欢)
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Corresponding author

Correspondence to Xing-hua Liu  (刘幸华).

Additional information

This work was supported by grants from the National Natural Science Foundation of China (No. 81301000), and Postdoctoral Science Foundation of China (No. 2016M590696).

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Yao, Es., Tang, Y., Liu, Xh. et al. TPPU protects tau from H2O2-induced hyperphosphorylation in HEK293/tau cells by regulating PI3K/AKT/GSK-3β pathway. J. Huazhong Univ. Sci. Technol. [Med. Sci.] 36, 785–790 (2016). https://doi.org/10.1007/s11596-016-1662-z

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  • DOI: https://doi.org/10.1007/s11596-016-1662-z

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