Oncotarget

Research Papers: Gerotarget (Focus on Aging):

COX-2 metabolic products, the prostaglandin I2 and F, mediate the effects of TNF-α and Zn2+ in stimulating the phosphorylation of Tau

Yue Wang, Pei-Pei Guan, Xin Yu, Yan-Su Guo, Ying-Jie Zhang, Zhan-You Wang and Pu Wang _

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Oncotarget. 2017; 8:99296-99311. https://doi.org/10.18632/oncotarget.21853

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Abstract

Yue Wang1,2, Pei-Pei Guan1, Xin Yu1, Yan-Su Guo3,4, Ying-Jie Zhang5,6, Zhan-You Wang1 and Pu Wang1

1 College of Life and Health Sciences, Northeastern University, Shenyang, P.R. China

2 Department of Tissue Culture, Liaoning University of Traditional Chinese Medicine, Shenyang, P.R. China

3 Key laboratory of Hebei Neurology, Hebei Medical University, Shijiazhuang, P.R. China

4 Institute of Cardiocerebrovascular Disease, Hebei Medical University, Shijiazhuang, P.R. China

5 College of Biology, Hunan University, Changsha, P.R. China

6 Shenzhen Institute, Hunan University, Shenzhen, P.R. China

Correspondence to:

Pu Wang, email:

Zhan-You Wang, email:

Keywords: cyclooxygenase-2; prostaglandins; tumor necrosis factor α; zinc transporter 3; tau phosphorylation

Received: June 08, 2017 Accepted: October 02, 2017 Published: October 16, 2017

Abstract

Although the roles of cyclooxygenase-2 (COX-2) and prostaglandins (PGs) in regulating amyloid precursor protein (APP) cleavage and β-amyloid protein (Aβ) production have been the subjects of numerous investigations, their effects on tau phosphorylation have been largely overlooked. Using human TauP301S transgenic (Tg) mice as in vivo model, our results demonstrated that PGI2 and PGF mediated the effects of tumor necrosis factor α (TNF-α) and Zinc ions (Zn2+) on upregulating the phosphorylation of tau via the PI3-K/AKT, ERK1/2 and JNK/c-Jun signaling pathways. Specifically, we initially found that high level of Zn2+ upregulates the expression of COX-2 via stimulating the activity of TNF-α in a zinc transporter 3 (ZnT3)-dependent mechanism. COX-2 upregulation then stimulates the phosphorylation of tau at both Ser 202 and Ser 400/Thr 403/Ser 404 via PGI2 and F treatment either in i.c.v.-injected mice or in n2a cells. Using n2a cells as in vitro model, we further revealed critical roles for the PI3-K/AKT, ERK1/2 and JNK/c-Jun pathways in mediating the effects of PGI2 and F in the phosphorylation of tau. Finally, NS398 treatment delayed the onset of cognitive decline in TauP301S Tg mice according to the nest construction or limb clasping test.


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