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Magnesium ion influx reduces neuroinflammation in Aβ precursor protein/Presenilin 1 transgenic mice by suppressing the expression of interleukin-1β

Cellular & Molecular Immunology volume 14, pages 451–464 (2017)Cite this article

Abstract

Alzheimer’s disease (AD) has been associated with magnesium ion (Mg2+) deficits and interleukin-1β (IL-1β) elevations in the serum or brains of AD patients. However, the mechanisms regulating IL-1β expression during Mg2+ dyshomeostasis in AD remain unknown. We herein studied the mechanism of IL-1β reduction using a recently developed compound, magnesium-L-threonate (MgT). Using human glioblastoma A172 and mouse brain D1A glial cells as an in vitro model system, we delineated the signaling pathways by which MgT suppressed the expression of IL-1β in glial cells. In detail, we found that MgT incubation stimulated the activity of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) and peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathways by phosphorylation, which resulted in IL-1β suppression. Simultaneous inhibition of the phosphorylation of ERK1/2 and PPARγ induced IL-1β upregulation in MgT-stimulated glial cells. In accordance with our in vitro data, the intracerebroventricular (i.c.v) injection of MgT into the ventricles of APP/PS1 transgenic mice and treatment of Aβ precursor protein (APP)/PS1 brain slices suppressed the mRNA and protein expression of IL-1β. These in vivo observations were further supported by the oral administration of MgT for 5 months. Importantly, Mg2+ influx into the ventricles of the mice blocked the effects of IL-1β or amyloid β-protein oligomers in the cerebrospinal fluid. This reduced the stimulation of IL-1β expression in the cerebral cortex of APP/PS1 transgenic mice, which potentially contributed to the inhibition of neuroinflammation.

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Acknowledgements

This work was supported in part or in whole by the National Natural Science Foundation of China (CN) (31571064, 81500934, 31300777, and 31371091), the National Natural Science Foundation of Liaoning, China (2015020662) the Fundamental Research Funds of China (N142004002 and N130120002) and the Liaoning Provincial Talent Support Program (LJQ2013029). We would like to acknowledge Andrew C. McCourt for critical reading and linguistic revision of the manuscript.

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  1. Pu Wang and Xin Yu: These authors contributed equally to this work.

  2. P Wang, College of Life and Health Sciences, Northeastern University, No. 3-11 Wenhua Road, Shenyang 110819, P. R. China. E-mail: wangpu@mail.neu.edu.cn

  3. Z-Y Wang, wangzy@mail.neu.edu.cn

Authors and Affiliations

  1. College of Life and Health Sciences, Northeastern University, Shenyang, P. R. China

    Pu Wang, Xin Yu, Pei-Pei Guan, Jing-Wen Guo, Yue Wang, Yan Zhang, Hang Zhao & Zhan-You Wang

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Wang, P., Yu, X., Guan, PP. et al. Magnesium ion influx reduces neuroinflammation in Aβ precursor protein/Presenilin 1 transgenic mice by suppressing the expression of interleukin-1β. Cell Mol Immunol 14, 451–464 (2017). https://doi.org/10.1038/cmi.2015.93

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