Department of Biomedical Engineering, University of North Texas, 3940 N Elm St, Denton, TX, 76207, USA.
Department of Biomedical Engineering, City College of the City University of New York, 160 Convent Ave, New York, NY, 10031, USA.
Mol Neurobiol. 2018 Sep;55(9):7118-7131. doi: 10.1007/s12035-018-0896-0. Epub 2018 Jan 30.
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 Mg 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/cm, 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.
镁缺乏是阿尔茨海默病（AD）的危险因素，其潜在机制仍不清楚。在这里，我们提供了第一个证据，即升高的镁水平显著降低了血脑屏障（BBB）的通透性，并调节了其在体外的功能。瞬时受体电位 melastatin 7（TRPM7）和镁转运体亚型 1（MagT1）是两种主要的细胞受体，介导细胞外镁进入细胞。升高的镁水平还通过低密度脂蛋白受体相关蛋白（LRP）和磷脂结合网格蛋白组装蛋白（PICALM）诱导 Aβ 从脑侧向血液侧的快速清除，通过 BBB 胞吞作用，而减少 Aβ 从血液侧向脑侧的内流，涉及晚期糖基化终产物受体（RAGE）和 caveolae。镁增强了 BBB 屏障特性和 LRP1 和 PICALM 的整体表达，同时降低了 RAGE 和 caveolin-1 的表达。AP 到 BL 以及反之亦然的稳态 Aβ 通量在初始加入生理浓度游离 Aβ 约 30 分钟后达到 18 和 0.27 fmol/min/cm 的平衡。敲低 caveolin-1 或破坏 caveolae 膜微区会显著减少 RAGE 介导的内流，但不会减少 LRP1 介导的 Aβ 外流。血管内皮生长因子（VEGF）刺激内皮细胞会增强 caveolin-1 磷酸化和 RAGE 表达。共免疫沉淀表明 RAGE，但不是 LRP1，与 caveolin-1 物理相关。因此，镁可以通过增加 LRP1 和 PICALM 的表达，同时降低 RAGE 和 caveolin-1 的水平，降低 BBB 的通透性，并促进 Aβ 从脑侧通过 BBB 清除。
