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Anti-diabetic vanadyl complexes reduced Alzheimer’s disease pathology independent of amyloid plaque deposition

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Abstract

Association of Alzheimer’s disease (AD) with cerebral glucose hypometabolism, likely due to impairments of insulin signaling, has been reported recently, with encouraging results when additional insulin is provided to AD patients. Here, we tested the potential effects of the anti-diabetic vanadium, vanadyl (IV) acetylacetonate (VAC), on AD in vitro and in vivo models. The experimental results showed that VAC at sub-micromolar concentrations improved the viability of neural cells with or without increased β-amyloid (Aβ) burden; and in APP/PS1 transgenic mice, VAC treatment (0.1 mmol kg−1 d−1) preserved cognitive function and attenuated neuron loss, but did not reduce brain Aβ plaques. Further studies revealed that VAC attenuated Aβ pathogenesis by (i) activation of the PPARγ-AMPK signal transduction pathway, leading to improved glucose and energy metabolism; (ii) up-regulation of the expression of glucose-regulated protein 75 (Grp75), thus suppressing p53-mediated neuronal apoptosis under Aβ-related stresses; and (iii) decreasing toxic soluble Aβ peptides. Overall, our work suggested that vanadyl complexes may have great potential for effective therapeutic treatment of AD.

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Acknowledgements

We thank Dr. Zengqiang Yuan at the Institute of Biophysics, Chinese Academy of Sciences for providing the three SH-SY5Y cells and kind assistances in cell culture. This work was supported by National Natural Science Foundation of China (21571006, 21771010), Beijing Municipal Science & Technology Commission (A61120-01) and the “Strategic Priority Research Program” of the Chinese Academy of Sciences (XDA 12040101).

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  1. The State Key Laboratories of Natural and Biomimetic Drugs and Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, China

    Yaqiong Dong, Yue Zhang, Chang Tan, Xue Li, Lan Yuan & Xiaoda Yang

  2. Department of Pathology, University of Washington School of Medicine, Seattle, WA, 98104, USA

    Tessandra Stewart, Min Shi, Aanchal Mehrotra & Jing Zhang

  3. Department of Pathology, School of Basic Medical Sciences and Peking University Third Hospital, Peking University Health Science Center, Beijing, 100191, China

    Jing Zhang

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  1. Yaqiong Dong
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Dong, Y., Stewart, T., Zhang, Y. et al. Anti-diabetic vanadyl complexes reduced Alzheimer’s disease pathology independent of amyloid plaque deposition. Sci. China Life Sci. 62, 126–139 (2019). https://doi.org/10.1007/s11427-018-9350-1

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