Ronco Virginia, Grolla Ambra A, Glasnov Toma N, Canonico Pier Luigi, Verkhratsky Alexei, Genazzani Armando A, Lim Dmitry
Department of Pharmaceutical Sciences, Università degli Studi del Piemonte Orientale "Amedeo Avogadro", 28100 Novara, Italy.
Christian Doppler Laboratory for Flow Chemistry (CDLFC), Institute of Chemistry, Karl-Franzens-University Graz, Heinrichstrasse 28, A-8010 Graz, Austria.
Cell Calcium. 2014 Apr;55(4):219-29. doi: 10.1016/j.ceca.2014.02.016. Epub 2014 Mar 2.
In Alzheimer's disease (AD), astrocytes undergo complex morphological and functional changes that include early atrophy, reactive activation and Ca(2+) deregulation. Recently, we proposed a mechanism by which nanomolar Aβ42 deregulates mGluR5 and InsP3 receptors, the key elements of astrocytic Ca(2+) signalling toolkit. To evaluate the specificity of these changes, we have now investigated whether the effects of Aβ42 on Ca(2+) signalling machinery can be reproduced by pro-inflammatory agents (TNFα, IL-1β, LPS). Here we report that Aβ42 (100nM, 72h) significantly increased mRNA levels of mGluR5, InsP3R1 and InsP3R2, whereas pro-inflammatory agents reduced expression of these specific mRNAs. Furthermore, DHPG-induced Ca(2+) signals and store operated Ca(2+) entry (SOCE) were augmented in Aβ42-treated cells due to up-regulation of a set of Ca(2+) signalling-related genes including TRPC1 and TRPC4. Opposite changes were observed when astrocytes were treated with TNFα, IL-1β and LPS. Last, the effects observed on SOCE by treating wild-type astrocytes with Aβ42 were also identified in untreated astrocytes from 3×Tg-AD animals, suggesting a link to the AD pathology. Our results demonstrate that effects of Aβ42 on astrocytic Ca(2+) signalling differ from and may contrast to the effects of pro-inflammatory agents.
在阿尔茨海默病（AD）中，星形胶质细胞会发生复杂的形态和功能变化，包括早期萎缩、反应性激活和钙离子（Ca(2+)）调节异常。最近，我们提出了一种机制，即纳摩尔浓度的淀粉样β蛋白42（Aβ42）会使代谢型谷氨酸受体5（mGluR5）和肌醇三磷酸受体（InsP3受体）失调，而这两种受体是星形胶质细胞Ca(2+)信号传导工具包的关键元件。为了评估这些变化的特异性，我们现在研究了促炎因子（肿瘤坏死因子α（TNFα）、白细胞介素1β（IL-1β）、脂多糖（LPS））是否能重现Aβ42对Ca(2+)信号传导机制的影响。在此我们报告，Aβ42（100纳摩尔，72小时）显著增加了mGluR5、InsP3R1和InsP3R2的mRNA水平，而促炎因子则降低了这些特定mRNA的表达。此外，由于包括瞬时受体电位通道蛋白1（TRPC1）和瞬时受体电位通道蛋白4（TRPC4）在内的一组Ca(2+)信号传导相关基因的上调，在Aβ42处理的细胞中，二羟苯甘氨酸（DHPG）诱导的Ca(2+)信号和储存操纵性Ca(2+)内流（SOCE）增强。当星形胶质细胞用TNFα、IL-1β和LPS处理时，观察到相反的变化。最后，在用Aβ42处理野生型星形胶质细胞时观察到的对SOCE的影响，在来自3×Tg-AD动物的未处理星形胶质细胞中也得到了证实，这表明与AD病理存在关联。我们的结果表明，Aβ42对星形胶质细胞Ca(2+)信号传导的影响与促炎因子的影响不同，甚至可能相反。
