Magnesium ion influx reduces neuroinflammation in Aβ precursor protein/Presenilin 1 transgenic mice by suppressing the expression of interleukin-1β
Magnesium ion influx reduces neuroinflammation in Aβ precursor protein/Presenilin 1 transgenic mice by suppressing the expression of interleukin-1β
复制标题
镁离子流入通过抑制白介素-1β 的表达来减少 Abeta 前体蛋白/早老素 1 转基因小鼠的神经炎症。
DOI：
10.1038/cmi.2015.93
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发表时间：
2017-05-01
影响因子：
24.1
通讯作者：
Wang, Zhan-You
中科院分区：
文献类型：
--
作者：
Wang, Pu;Yu, Xin;Wang, Zhan-You
阿尔茨海默病（AD）与AD患者血清或脑中镁离子（Mg 2+）缺乏和白细胞介素-1 β（IL-1 β）升高有关。然而，在AD中Mg（2+）稳态失调期间调节IL-1 β表达的机制仍然未知。我们在此研究了使用最近开发的化合物L-苏糖酸镁（MgT）降低IL-1 β的机制。使用人胶质母细胞瘤A172和小鼠脑D1 A胶质细胞作为体外模型系统，我们描绘了MgT抑制胶质细胞中IL-1 β表达的信号通路。详细地，我们发现MgT孵育通过磷酸化刺激细胞外信号调节蛋白激酶1和2（ERK 1/2）和过氧化物酶体增殖物激活受体γ（PPAR γ）信号通路的活性，这导致IL-1 β抑制。在MgT刺激的神经胶质细胞中，同时抑制ERK 1/2和PPAR γ的磷酸化诱导IL-1 β上调。根据我们的体外实验数据，侧脑室（i.c.v）注射MgT到APP/PS1转基因小鼠的脑室和Ab前体蛋白（APP）/PS1脑片处理抑制IL-1 β的mRNA和蛋白质表达。这些体内观察结果进一步得到口服给予MgT 5个月的支持。重要的是，Mg（2+）流入小鼠脑室阻断了脑脊液中IL-1 β或淀粉样β蛋白寡聚体的作用。这减少了APP/PS1转基因小鼠大脑皮层中IL-1 β表达的刺激，这可能有助于抑制神经炎症。Cellular & Molecular Immunology（2017）在线发表2015年11月9日
Alzheimer's disease (AD) has been associated with magnesium ion (Mg2+) deficits and interleukin-1 beta (IL-1 beta) elevations in the serum or brains of AD patients. However, the mechanisms regulating IL-1 beta expression during Mg (2+) dyshomeostasis in AD remain unknown. We herein studied the mechanism of IL-1 beta 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-1 beta 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 (PPAR gamma) signaling pathways by phosphorylation, which resulted in IL-1 beta suppression. Simultaneous inhibition of the phosphorylation of ERK1/2 and PPAR gamma induced IL-1 beta 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 Ab precursor protein (APP)/PS1 brain slices suppressed the mRNA and protein expression of IL-1 beta. These in vivo observations were further supported by the oral administration of MgT for 5 months. Importantly, Mg (2+) influx into the ventricles of the mice blocked the effects of IL-1 beta or amyloid beta-protein oligomers in the cerebrospinal fluid. This reduced the stimulation of IL-1 beta expression in the cerebral cortex of APP/PS1 transgenic mice, which potentially contributed to the inhibition of neuroinflammation. Cellular & Molecular Immunology (2017) published online 9 November 2015