Ca(2+)-dependent endoplasmic reticulum stress correlation with astrogliosis involves upregulation of KCa3.1 and inhibition of AKT/mTOR signaling.
Ca(2+)-dependent endoplasmic reticulum stress correlation with astrogliosis involves upregulation of KCa3.1 and inhibition of AKT/mTOR signaling.
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Ca2 依赖性内质网应激与星形胶质细胞增生的相关性涉及 KCa3.1 的上调和 AKT/mTOR 信号传导的抑制
DOI：
10.1186/s12974-018-1351-x
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发表时间：
2018-11-15
影响因子：
9.3
通讯作者：
Chen H
中科院分区：
文献类型：
--
作者：
Yu Z;Dou F;Wang Y;Hou L;Chen H
中电导Ca 2+激活的K+通道KCa 3.1最近被证明控制阿尔茨海默病（AD）中反应性星形胶质细胞增生（RA）的表型转换。采用免疫印迹和免疫组化方法检测AD患者和APP/PS 1小鼠模型脑内KCa 3.1通道的表达和细胞定位。APP/PS1小鼠和KCa 3.1-/-/APP/PS1小鼠进行Morris水迷宫测试以评估空间记忆缺陷。通过免疫染色测量胶质细胞活化和神经元损失。采用Fluo-4AM检测β-淀粉样蛋白（Aβ）诱导的星形胶质细胞反应性损伤后细胞内钙离子浓度的变化。在Aβ刺激的AD患者和APP/PS1 AD小鼠的原代星形胶质细胞和脑裂解物中，KCa 3.1表达与内质网（ER）应激和未折叠蛋白反应（UPR）显著相关。在原代星形胶质细胞中，KCa 3.1通道通过与Ca 2+通道Orai 1相互作用来调节钙库操纵的Ca 2+内流（SOCE）。KCa 3.1的基因缺失或药物阻断通过蛋白激酶B（AKT）信号通路保护星形胶质细胞免受SOCE诱导的Ca 2+超载和ER应激。重要的是，KCa3.1的基因缺失或阻断恢复了体内和体外雷帕霉素信号传导的AKT/机制靶点。与这些体外数据一致，ER应激标志物78-kDa葡萄糖调节蛋白和CCAAT/增强子结合蛋白同源蛋白以及RA标志物胶质细胞酸性蛋白的表达水平在APP/PS1 AD小鼠模型中增加。在KCa3.1−/−/APP/PS1小鼠中消除KCa3.1纠正了这些异常反应。此外，与APP/PS1小鼠相比，KCa3.1−/−/APP/PS1小鼠的海马中的胶质细胞活化和神经炎症减弱。此外，APP/PS1小鼠的记忆缺陷和神经元丢失在KCa3.1−/−/APP/PS1小鼠中得到逆转。总体而言，这些结果表明，KCa3.1参与调节星形胶质细胞中的Ca 2+稳态和UPR和ER应激的衰减，从而导致记忆缺陷和神经元丢失。
The intermediate-conductance Ca2+-activated K+ channel KCa3.1 was recently shown to control the phenotype switch of reactive astrogliosis (RA) in Alzheimer’s disease (AD). KCa3.1 channels expression and cell localization in the brains of AD patients and APP/PS1 mice model were measured by immunoblotting and immunostaining. APP/PS1 mice and KCa3.1−/−/APP/PS1 mice were subjected to Morris water maze test to evaluate the spatial memory deficits. Glia activation and neuron loss was measured by immunostaining. Fluo-4AM was used to measure cytosolic Ca2+ level in β-amyloid (Aβ) induced reactive astrocytes in vitro. KCa3.1 expression was markedly associated with endoplasmic reticulum (ER) stress and unfolded protein response (UPR) in both Aβ-stimulated primary astrocytes and brain lysates of AD patients and APP/PS1 AD mice. The KCa3.1 channel was shown to regulate store-operated Ca2+ entry (SOCE) through an interaction with the Ca2+ channel Orai1 in primary astrocytes. Gene deletion or pharmacological blockade of KCa3.1 protected against SOCE-induced Ca2+ overload and ER stress via the protein kinase B (AKT) signaling pathway in astrocytes. Importantly, gene deletion or blockade of KCa3.1 restored AKT/mechanistic target of rapamycin signaling both in vivo and in vitro. Consistent with these in vitro data, expression levels of the ER stress markers 78-kDa glucose-regulated protein and CCAAT/enhancer-binding protein homologous protein, as well as that of the RA marker glial fibrillary acidic protein were increased in APP/PS1 AD mouse model. Elimination of KCa3.1 in KCa3.1−/−/APP/PS1 mice corrected these abnormal responses. Moreover, glial activation and neuroinflammation were attenuated in the hippocampi of KCa3.1−/−/APP/PS1 mice, as compared with APP/PS1 mice. In addition, memory deficits and neuronal loss in APP/PS1 mice were reversed in KCa3.1−/−/APP/PS1 mice. Overall, these results suggest that KCa3.1 is involved in the regulation of Ca2+ homeostasis in astrocytes and attenuation of the UPR and ER stress, thus contributing to memory deficits and neuronal loss.
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影响因子：
4.7
作者：
Chow SK;Yu D;Macdonald CL;Buibas M;Silva GA
通讯作者：
Silva GA
DOI：
10.1126/science.1169096
发表时间：
2009-02-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kuchibhotla KV;Lattarulo CR;Hyman BT;Bacskai BJ
通讯作者：
Bacskai BJ
影响因子：
16.6
作者：
Chiang EY;Li T;Jeet S;Peng I;Zhang J;Lee WP;DeVoss J;Caplazi P;Chen J;Warming S;Hackos DH;Mukund S;Koth CM;Grogan JL
通讯作者：
Grogan JL
影响因子：
5.3
作者：
Bouhy, Delphine;Ghasemlou, Nader;David, Samuel
通讯作者：
David, Samuel
影响因子：
6.1
作者：
Chen, Cheng-Lung;Liao, Jiunn-Wang;Pao, Li-Heng
通讯作者：
Pao, Li-Heng