Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
Department of Medical Sciences, University of Ferrara, Ferrara, Italy.
Sci Rep. 2019 Apr 24;9(1):6475. doi: 10.1038/s41598-019-42931-2.
Previous data from our laboratory show that expression of the P2X7 receptor (P2X7R) is needed for amyloid β (Aβ)-stimulated microglia activation and IL-1β release in vitro and in vivo. We also showed that Aβ-dependent stimulation is inhibited by the dihydropyridine nimodipine at an intracellular site distal to the P2X7R. In the present study, we used the N13 microglia cell line and mouse primary microglia from wt and P2rx7-deleted mice to test the effect of nimodipine on amyloid β (Aβ)-dependent NLRP3 inflammasome expression and function, and on mitochondrial energy metabolism. Our data show that in microglia Aβ causes P2X7R-dependent a) NFκB activation; b) NLRP3 inflammasome expression and function; c) mitochondria toxicity; and these changes are fully inhibited by nimodipine. Our study shows that nimodipine is a powerful blocker of cell damage caused by monomeric and oligomeric Aβ, points to the mitochondria as a crucial target, and underlines the permissive role of the P2X7R.
先前我们实验室的数据表明，P2X7 受体（P2X7R）的表达对于体外和体内淀粉样β（Aβ）刺激小胶质细胞激活和白细胞介素-1β（IL-1β）释放是必需的。我们还表明，二氢吡啶类尼莫地平（nimodipine）可以在 P2X7R 远端的细胞内位点抑制 Aβ依赖性刺激。在本研究中，我们使用 N13 小胶质细胞系和来自野生型（wt）和 P2rx7 基因敲除（P2rx7-deleted）小鼠的原代小胶质细胞，测试了尼莫地平对 Aβ依赖性 NLRP3 炎性体表达和功能以及线粒体能量代谢的影响。我们的数据表明，在小胶质细胞中，Aβ引起 P2X7R 依赖性：a）NFκB 激活；b）NLRP3 炎性体表达和功能；c）线粒体毒性；而这些变化完全被尼莫地平抑制。我们的研究表明，尼莫地平是由单体和寡聚体 Aβ引起的细胞损伤的有效抑制剂，指出线粒体是一个关键靶点，并强调了 P2X7R 的许可作用。
