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Trans-resveratrol Inhibits Tau Phosphorylation in the Brains of Control and Cadmium Chloride-Treated Rats by Activating PP2A and PI3K/Akt Induced-Inhibition of GSK3β

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Abstract

This study investigated if resveratrol (RES) can protect against cadmium chloride (CdCl2)-induced memory loss and Tau protein hyperphosphorylation in rats and explored its effect on AMPK/PI3K/Akt signaling pathway. Rats (n = 10/group) were divided into seven groups as: control; control + DMSO; control + LY294002, a selective PI3K inhibitor (0.25 µg/100 g, i.p); control + RES (300 mg/kg, orally); CdCl2 (5 mg/kg, orally); CdCl2 + RES and CdCl2 + RES + LY294002. All treatments were carried out for 30 consecutive days on a daily basis. RES improved both short and long-term memory as analyzed by novel object recognition task and significantly increased brain levels of glutathione in both control and CdCl2-treated rats. It also inhibited ROS levels of malondialdehyde in the brains of CdCl2-treated rats. In both groups, RES decreased the phosphorylation rate of Tau at Ser199 and Ser296. Concomitantly, it significantly increased protein levels of p-GSK3β (Ser9) and p-PP2A and decreased p-GSK3β (Tyr216). Also, RES activated PI3K/Akt signaling pathway in both control and CdCl2 treated rats by increasing levels of p-PI3K (Tyr607) and p-Akt (Ser473). This was concomitant with significant increase in the levels of AMPK and p-AMPK, known upstream regulators of PI3K/Akt signaling pathway. Interestingly, all the above listed beneficial effects of RES, except their effect on AMPK/p-AMPK, were completely abolished in CdCl2 + RES + LY294002-treated rats. In conclusion, in addition to its antioxidant potential, RES inhibits Tau phosphorylation in rat’s brain by activating PP2A protein and AMPK/PI3K/Akt-induced inhibition of GSK3β.

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Acknowledgements

The authors would like to thank Mr. Mahmoud Alkhateeb from King Saud University for Health Sciences for his partial contribution to this study. They would like to thank the animal facility staff at King Khalid University for taking of animals during the experimental procedure.

Funding

The authors extend their appreciation to the Deanship of Scientific Research at King Khalid University for funding this work through General Research Project under grant number (201/39).

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  1. Department of Biology, College of Science, King Khalid University, Abha, Saudi Arabia

    Ali A. Shati & Mohammad Y. Alfaifi

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  1. Ali A. Shati
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Both AS and MA contributed equally to this work. AS and MA designed the experimental procedure and supervised the treatment and sample collections. MA performed the behavioral analysis and measured some of the biochemical parameters of this study. AS performed all the western blotting measurements. AS and MA collected the data, analyzed them and graphed the data. AS wrote the draft of the manuscript and MA finalized the final version.

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Correspondence to Ali A. Shati.

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Shati, A.A., Alfaifi, M.Y. Trans-resveratrol Inhibits Tau Phosphorylation in the Brains of Control and Cadmium Chloride-Treated Rats by Activating PP2A and PI3K/Akt Induced-Inhibition of GSK3β. Neurochem Res 44, 357–373 (2019). https://doi.org/10.1007/s11064-018-2683-8

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