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Rapamycin Ameliorates Cognitive Impairments and Alzheimer’s Disease-Like Pathology with Restoring Mitochondrial Abnormality in the Hippocampus of Streptozotocin-Induced Diabetic Mice

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Abstract

Alzheimer’s disease (AD) and diabetes mellitus (DM) share common pathophysiological findings, in particular, the mammalian target of rapamycin (mTOR) has been strongly implied to link to AD, while it also plays a key role in the insulin signaling pathway. However, the mechanism of how DM and AD is coupled remains elusive. In the present study, we found that streptozotocin (STZ)-induced DM mice significantly increased the levels P-mTOR Ser2448, P-p70S6K Thr389, P-tau Ser356 and Aβ levels (Aβ oligomer/monomer), as well as the levels of Drp1 and p-Drp1 S616 (mitochondrial fission proteins) are increased, whereas no change was found in the expression of Opa1, Mfn1 and Mfn2 (mitochondrial fusion proteins) compared with control mice. Moreover, the expression of 4-HNE and 8-OHdG showed an aberrant increase in the hippocampus of STZ-induced DM mice that is associated with a decreased capacity of spatial memory and a loss of synapses. Rapamycin, an inhibitor of mTOR, rescued the STZ-induced increases in mTOR/p70S6K activities, tau phosphorylation and Aβ levels, as well as mitochondria abnormality and cognitive impairment in mice. These findings imply that rapamycin prevents cognitive impairment and protects hippocampus neurons from AD-like pathology and mitochondrial abnormality, and also that rapamycin treatment could normalize these STZ-induced alterations by decreasing hippocampus mTOR/p70S6K hyperactivity.

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Acknowledgements

This work was supported by Chinese National Natural Science Foundation (81560241, 81960265), the Foundation for Science and Technology projects in Guizhou ([2017]1014, LH [2017]7156, [2018]1009, [2018]5752, [2020]1Y354), the Foundation for Science and Technology projects in Guiyang ([2019]9-2-7) and the Foundation of the Education Department of Guizhou Province (KY [2016]035).

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  1. Yuanting Ding and Heng Liu have equally contributed to the manuscript.

Authors and Affiliations

  1. Department of Clinical Research Center, The First Affliated Hospital of Guizhou University of Traditional Chinese Medicine, Baoshan Road No.71, Guiyang, 550001, Guizhou, China

    Yuanting Ding, Mofei Cen, Yuxiang Tao, Chencen Lai & Zhi Tang

  2. Department of Anesthesiology, Tongren Municipal People’s Hospital, Tongren, 554300, Guizhou, China

    Heng Liu

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  1. Yuanting Ding
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Correspondence to Zhi Tang.

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Ding, Y., Liu, H., Cen, M. et al. Rapamycin Ameliorates Cognitive Impairments and Alzheimer’s Disease-Like Pathology with Restoring Mitochondrial Abnormality in the Hippocampus of Streptozotocin-Induced Diabetic Mice. Neurochem Res 46, 265–275 (2021). https://doi.org/10.1007/s11064-020-03160-6

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