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Magnesium Reduces Blood-Brain Barrier Permeability and Regulates Amyloid-β Transcytosis

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Abstract

Poor Mg status is a risk factor for Alzheimer’s disease (AD), and the underlying mechanisms remain elusive. Here, we provided the first evidence that elevated Mg levels significantly reduced the blood-brain barrier (BBB) permeability and regulated its function in vitro. Transient receptor potential melastatin 7 (TRPM7) and magnesium transporter subtype 1 (MagT1) were two major cellular receptors mediating entry of extracellular Mg2+ into the cells. Elevated Mg levels also induced an accelerated clearance of amyloid-β peptide (Aβ) from the brain to the blood side via BBB transcytosis through low-density lipoprotein receptor-related protein (LRP) and phosphatidylinositol binding clathrin assembly protein (PICALM), while reduced the influx of Aβ from the blood to the brain side involving receptor for advanced glycation end products (RAGE) and caveolae. Mg enhanced BBB barrier properties and overall expression of LRP1 and PICALM whereas reduced that of RAGE and caveolin-1. Apical-to-basolateral and vice versa steady-state Aβ flux achieved an equilibrium of 18 and 0.27 fmol/min/cm2, respectively, about 30 min after the initial addition of physiological levels of free Aβ. Knockdown of caveolin-1 or disruption of caveolae membrane microdomains reduced RAGE-mediated influx significantly, but not LRP1-mediated efflux of Aβ. Stimulating endothelial cells with vascular endothelial growth factor (VEGF) enhanced caveolin-1 phosphorylation and RAGE expression. Co-immunoprecipitation demonstrated that RAGE, but not LRP1, was physically associated with caveolin-1. Thus, Mg can reduce BBB permeability and promote BBB clearance of Aβ from the brain by increasing the expression of LRP1 and PICALM while reducing the level of RAGE and caveolin-1.

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Acknowledgements

We thank Dr. Yadong Wang from the Cornell University for his advice on experimental design and manuscript preparations. We also thank Drs. Berislav V. Zlokovic, Abhay Sagare, and Zhen Zhao from the University of Southern California as well as Dr. Hongmei Li from the Mayo Clinic for their constructive comments on the study and manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Funding

This work was supported by the National Institutes of Health [grant number SC3GM113762].

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Authors and Affiliations

  1. Department of Biomedical Engineering, University of North Texas, 3940 N Elm St, Denton, TX, 76207, USA

    Donghui Zhu & Yingchao Su

  2. Department of Biomedical Engineering, City College of the City University of New York, 160 Convent Ave, New York, NY, 10031, USA

    Bingmei Fu

  3. Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, 422 Siming S Rd, Siming Qu, Xiamen Shi, Fujian Sheng, 361005, China

    Huaxi Xu

  4. Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, 10901 N Torrey Pines Rd, La Jolla, CA, 92037, USA

    Huaxi Xu

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  1. Donghui Zhu
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Zhu, D., Su, Y., Fu, B. et al. Magnesium Reduces Blood-Brain Barrier Permeability and Regulates Amyloid-β Transcytosis. Mol Neurobiol 55, 7118–7131 (2018). https://doi.org/10.1007/s12035-018-0896-0

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