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mTOR-mediated hyperphosphorylation of tau in the hippocampus is involved in cognitive deficits in streptozotocin-induced diabetic mice

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Abstract

Abnormal levels of mammalian target of rapamycin (mTOR) signaling have been recently implicated in the pathophysiology of neurodegenerative diseases, such as Alzheimer’s disease (AD). However, the implication of mTOR in diabetes mellitus (DM)-related cognitive dysfunction still remains unknown. In the present study, we found that phosphorylated mTOR at Ser2448, phosphorylated p70S6K at Thr421/Ser424 and phosphorylated tau at Ser396 were significantly increased in the hippocampus of streptozotocin (STZ)-induced diabetic mice when compared with control mice. A low dose of rapamycin was used to elucidate the role of mTOR signaling in DM-related cognitive deficit. Rapamycin restored abnormal mTOR/p70S6K signaling and attenuated the phosphorylation of tau protein in the hippocampus of diabetic mice. Furthermore, the spatial learning and memory function of diabetic mice significantly impaired compared with control mice, was also reversed by rapamycin. These findings indicate that mTOR/p70S6K signaling pathway is hyperactive in the hippocampus of STZ-induced diabetic mice and inhibiting mTOR signaling with rapamycin prevents the DM-related cognitive deficits partly through attenuating the hyperphosphorylation of tau protein.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 81170754 and 81373394) and the Open-End Fund for the Valuable and Precision Instruments of Central South University.

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Authors and Affiliations

  1. Department of Endocrinology, Xiang-Ya Hospital, Central South University, 87 Xiang-Ya Road, Changsha, Hunan, 410008, China

    Shan-lei Zhou, Jin-ju Ma, Xia-jie Shi & Jing Wu

  2. Department of Pharmaceutical Engineering, College of Chemistry and Chemical Engineering, Central South University, Changsha, China

    Shan Wang & Fang-yuan Min

  3. Department of Neurobiology, Care Sciences and SocietyKI-Alzheimer’s Disease Research Center, Karolinska Institutet, Novum, Huddinge, Sweden

    Erika Bereczki

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  1. Shan Wang
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  2. Shan-lei Zhou
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Correspondence to Jing Wu.

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Wang, S., Zhou, Sl., Min, Fy. et al. mTOR-mediated hyperphosphorylation of tau in the hippocampus is involved in cognitive deficits in streptozotocin-induced diabetic mice. Metab Brain Dis 29, 729–736 (2014). https://doi.org/10.1007/s11011-014-9528-1

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  • DOI: https://doi.org/10.1007/s11011-014-9528-1

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