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(−)-Epigallocatechin-3-gallate alleviates spatial memory impairment in APP/PS1 mice by restoring IRS-1 signaling defects in the hippocampus

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Abstract

Alzheimer’s disease (AD) fundamentally represents a metabolic disease associated with brain insulin resistance. TNF-α/c-Jun N-terminal kinase (JNK) signaling plays a central role in serine phosphorylation of insulin receptor substrate-1 (IRS-1). (−)-Epigallocatechin-3-gallate (EGCG), a potent antioxidant, has been verified to attenuate peripheral insulin resistance by reducing IRS-1 signaling blockage. This study aimed to investigate the effects and possible mechanisms of EGCG on central IRS-1 signaling in vivo. APP/PS1 mice were treated with EGCG, and spatial memory was assessed by the Morris water maze test. Levels of soluble and insoluble Aβ42 in the hippocampus were determined by ELISA. The activation of NF-α/JNK and IRS signaling was detected by immunohistochemistry and Western blot analysis. Our results showed that EGCG ameliorated the impaired learning and memory in APP/PS1 mice. Notably, we found a significant reduction of IRS-1pS636 level accompanied with decreased Aβ42 levels in the hippocampus of 13-month-old female APP/PS1 mice after treatment with EGCG (2 or 6 mg/kg/day) for 4 weeks. Furthermore, EGCG treatment inhibited TNF-α/JNK signaling and increased the phosphorylation of Akt and glycogen synthase kinase-3β in the hippocampus of APP/PS1 mice. In conclusion, our study provides evidence that long-term consumption of EGCG may alleviate AD-related cognitive deficits by effectively attenuating central insulin resistance.

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Acknowledgments

This study was supported by Natural Science Foundation of China (Grant No. 81172371); Social Development Research Projects of Science and Technology Department in Liaoning Province (Grant No. 2012225019); Science and Technology Research Funds of Liaoning Medical University for Youth (Grant No. Y2012z001); First Affiliated Hospital Science and Technology Research Funds of Liaoning Medical University (Grant No. FYK201205 and FY2012-01).

Conflict of interest

The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Department of Neurology, First Affiliated Hospital of China Medical University, No. 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, China

    Ning Jia, Sha Sha, Gui-Ru Ren & Yun-Peng Cao

  2. Department of Neurology, First Affiliated Hospital of Liaoning Medical University, Jinzhou, 121001, Liaoning Province, China

    Kun Han

  3. Department of VIP, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, Liaoning Province, China

    Jing-Jing Kong

  4. Department of Biochemistry, Liaoning Medical University, Jinzhou, 121001, Liaoning Province, China

    Xiu-Mei Zhang

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  1. Ning Jia
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  2. Kun Han
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  3. Jing-Jing Kong
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  4. Xiu-Mei Zhang
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  5. Sha Sha
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  7. Yun-Peng Cao
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Correspondence to Yun-Peng Cao.

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Jia, N., Han, K., Kong, JJ. et al. (−)-Epigallocatechin-3-gallate alleviates spatial memory impairment in APP/PS1 mice by restoring IRS-1 signaling defects in the hippocampus. Mol Cell Biochem 380, 211–218 (2013). https://doi.org/10.1007/s11010-013-1675-x

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  • DOI: https://doi.org/10.1007/s11010-013-1675-x

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