KCa3.1 deficiency attenuates neuroinflammation by regulating an astrocyte phenotype switch involving the PI3K/AKT/GSK3β pathway
KCa3.1 deficiency attenuates neuroinflammation by regulating an astrocyte phenotype switch involving the PI3K/AKT/GSK3β pathway
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KCa3.1 缺乏通过调节涉及 PI3K/AKT/GSK3β 途径的星形胶质细胞表型转换来减轻神经炎症
DOI：
10.1016/j.nbd.2019.104588
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发表时间：
2019-12
影响因子：
6.1
通讯作者：
Zhihua Yu
中科院分区：
文献类型：
--
作者：
Tianjiao Wei;Yanxia Wang;Weirong Xu;Yan Liu;Hongzhuan Chen;Zhihua Yu
神经炎症可诱导神经退行性疾病表型转换为反应性星形胶质细胞增生。钙激活钾通道（KCa3.1）在阿尔茨海默病和缺血性中风的星形胶质细胞增生过程中发生的表型转换中具有活性。在这里，转录组测序（RNA-Seq），免疫组织化学，蛋白质印迹，药理学阻断和钙成像被用来研究星形胶质细胞KCa3.1在神经炎症，Tau积累和胰岛素信号转导缺陷中的活性，在雄性野生型C57 BL/6和KCa3.1−/−敲除（KO）小鼠中，以及在原代星形胶质细胞培养中。KCa 3. 1缺陷可降低脂多糖（LPS）诱导的记忆缺陷、神经元丢失、胶质细胞活化、Tau磷酸化和胰岛素信号转导缺陷，星形胶质细胞中KCa 3. 1表达与LPS诱导的Orai 1钙库操纵的Ca 2+通道蛋白上调相关。在LPS诱导的反应性星形胶质细胞中，发现KCa3.1通道通过与Orai 1相互作用来调节钙库操作的Ca 2+过载。LPS对KCa 3. 1和Orai 1的影响通过PI 3 K/AKT/GSK 3 β和NF-κB信号通路间接促进了星形胶质细胞的凋亡。对主动翻译的RNA的RNA-Seq结果的无偏倚评估证实，大量星形胶质细胞多样性与KCa3.1缺乏相关。我们的研究结果表明，KCa 3.1通过PI 3 K/AKT/GSK 3 β和NF-κB信号通路调节星形胶质细胞变性介导的神经炎症、Tau积累和胰岛素信号转导缺陷，并在该神经炎症小鼠模型中促成神经元损失和记忆缺陷。
Neuroinflammation may induce a phenotype switch to reactive astrogliosis in neurodegenerative disorders. The calcium-activated potassium channel (KCa3.1) is active in the phenotypic switch that occurs during astrogliosis in Alzheimer's disease and ischemic stroke. Here, transcriptome sequencing (RNA-Seq), immunohistochemistry, western blotting, pharmacological blockade, and calcium imaging were used to investigate astrocyte KCa3.1 activity in neuroinflammation, Tau accumulation, and insulin signaling deficits in male wild-type C57BL/6 and KCa3.1−/−knockout (KO) mice, and in primary astrocyte cultures. KCa3.1 deficiency in KO mice decreased lipopolysaccharide (LPS)-induced memory deficits, neuronal loss, glial activation, Tau phosphorylation, and insulin signaling deficits in vivo.KCa3.1 expression in astrocytes was associated with LPS-induced upregulation of the Orai1 store-operated Ca2+channel protein. The KCa3.1 channel was found to regulate store-operated Ca2+overload through an interaction with Orai1 in LPS-induced reactive astrocytes. The LPS-induced effects on KCa3.1 and Orai1 indirectly promoted astrogliosis-related changes via the PI3K/AKT/GSK3β and NF-κB signaling pathways in vitro. Unbiased evaluation of RNA-Seq results for actively translated RNAs confirmed that substantial astrocyte diversity was associated with KCa3.1 deficiency. Our results suggest that KCa3.1 regulated astrogliosis-mediated neuroinflammation, Tau accumulation, and insulin signaling deficiency via PI3K/AKT/GSK3β and NF-κB signaling pathways, and contributing to neuronal loss and memory deficits in this neuroinflammation mouse model.
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DOI：
10.1523/jneurosci.6221-11.2012
发表时间：
2012-05-02
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Zamanian JL;Xu L;Foo LC;Nouri N;Zhou L;Giffard RG;Barres BA
通讯作者：
Barres BA
影响因子：
6.3
作者：
Calvo-Ochoa, Erika;Hernandez-Ortega, Karina;Arias, Clorinda
通讯作者：
Arias, Clorinda
影响因子：
4.8
作者：
Hartigan, JA;Johnson, GVW
通讯作者：
Johnson, GVW
影响因子：
20.3
作者：
Stocker, JW;De Franceschi, L;Brugnara, C
通讯作者：
Brugnara, C
DOI：
10.1016/j.jalz.2019.06.4616
发表时间：
2019-07
期刊：
Alzheimer's & Dementia
影响因子：
--
作者：
S. Liddelow;Kevin A. Guttenplan;L. Clarke;F. C. Bennett;Christopher J. Bohlen;Lucas Schirmer;Mariko L. Bennett-M
通讯作者：
S. Liddelow;Kevin A. Guttenplan;L. Clarke;F. C. Bennett;Christopher J. Bohlen;Lucas Schirmer;Mariko L. Bennett-M