N-methyl-D-aspartate receptor-mediated calcium overload and endoplasmic reticulum stress are involved in interleukin-1beta-induced neuronal apoptosis in rat hippocampus
N-methyl-D-aspartate receptor-mediated calcium overload and endoplasmic reticulum stress are involved in interleukin-1beta-induced neuronal apoptosis in rat hippocampus
复制标题
N-甲基-D-天冬氨酸受体介导的钙超载和内质网应激参与白介素-1β诱导的大鼠海马神经元凋亡
DOI：
10.1016/j.jneuroim.2017.03.005
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发表时间：
2017-06-15
影响因子：
3.3
通讯作者：
Song, Cai
中科院分区：
文献类型：
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作者：
Dong, Yilong;Kalueff, Allan V.;Song, Cai
白细胞介素（IL）-1β水平升高及其基因表达与阿尔茨海默病（AD）的病因有关。IL - 1β激活小胶质细胞并刺激谷氨酸能N - 甲基 - D - 天冬氨酸受体（NMDA受体）表达，从而扰乱细胞内Ca²⁺稳态。Ca²⁺失衡反过来可能引发内质网（ER）应激，导致整体兴奋性毒性和神经元死亡，诱发AD。然而，目前尚不清楚IL - 1β诱导的神经元凋亡是否由谷氨酸能系统、内质网应激和/或Ca²⁺功能障碍介导。本研究通过评估NMDA受体诱导的Ca²⁺过载以及NMDA介导的内质网应激，研究了NMDA受体（NMDAR）在内质网应激和IL - 1β诱发的神经元死亡中的作用。雄性Long Evans大鼠接受脑室内注射IL - 1β（有或无NMDA受体拮抗剂MK801），持续8天。采用高效液相色谱法（HPLC）测量谷氨酸浓度，通过实时荧光定量PCR和蛋白质印迹法评估小胶质细胞生物标志物和NMDAR的mRNA及蛋白质表达，以及Ca²⁺过载标志物（钙蛋白酶2，caplain2）和内质网应激标志物（葡萄糖调节蛋白78，GRP78，以及C/EBP同源蛋白 - 10，CHOP）。还使用TUNEL法评估海马神经元的凋亡情况。总体而言，IL - 1β诱导了强烈的神经元凋亡，同时伴有NMDAR、caplain2、GRP78和CHOP上调。MK801预处理显著减轻了神经元凋亡和NMDA的上调，也降低了GRP78和CHOP的表达。总之，这些结果表明IL - 1β可能通过NMDA受体介导的机制扰乱细胞内Ca²⁺稳态，从而通过增强内质网应激触发神经元凋亡。（C）2017爱思唯尔有限公司。保留所有权利。
Increased levels of interleukin (IL)-1 beta and its gene expression are implicated in the etiology of Alzheimer's disease (AD). IL-1 beta activates microglia and stimulates glutamatergic N-methyl-D-aspartate receptor NMDA receptor expression, thereby disturbing intracellular Ca2+ homeostasis. Ca2+ disequilibrium, in turn, may trigger endoplasmic reticulum (ER) stress, contributing to overall excitotoxicity and neuronal death that evoke AD. However, it is unclear whether IL-1 beta-induced neuronal apoptosis is mediated by the glutamatergic system, ER stress and/or Ca2+ dysfunction. The present study investigated the role of NMDA receptor (NMDAR) in ER stress and IL-1 beta-evoked neuronal death by assessing NMDAR-induced Ca2+ overload and NMDA-mediated ER stress. Male Long Evans rats were treated with IL-1 beta (with or without NMDAR antagonist MK801) injected intracerebroventricularly for 8 days. Glutamate concentration was measured by HPLC, and mRNA and protein expression of microglial biomarkers and NMDAR, as well as markers of Ca2+ overload (caplain2) and ER stress (glucose-regulated protein 78, GRP78, and C/EBP homologous protein-10, CHOP), were assessed by real-time PCR and western blot. Apoptosis was also evaluated in the hippocampal neurons using TUNEL Overall, IL-1 beta induced robust neuronal apoptosis, accompanied by upregulated NMDAR, caplain2, GRP78 and CHOP. MK801 pretreatment significantly attenuated neuronal apoptosis and NMDA up-regulation, also reducing GRP78 and CHOP expression. In summary, these results suggest that IL-1 beta may disturb intracellular Ca2+ homeostasis via NMDAR-mediated mechanism, thereby triggering neuronal apoptosis by enhancing ER stress. (C) 2017 Elsevier B.V. All rights reserved.