Amyloid β-dependent mitochondrial toxicity in mouse microglia requires P2X7 receptor expression and is prevented by nimodipine

被引：55

作者：

Chiozzi, Paola ^{[1
]}

Sarti, Alba Clara ^{[1
]}

Sanz, Juana M. ^{[2
]}

Giuliani, Anna Lisa ^{[1
]}

Adinolfi, Elena ^{[1
]}

Vultaggio-Poma, Valentina ^{[1
]}

Falzoni, Simonetta ^{[1
]}

Di Virgilio, Francesco ^{[1
]}

机构：

[1] Univ Ferrara, Dept Morphol Surg & Expt Med, Ferrara, Italy

[2] Univ Ferrara, Dept Med Sci, Ferrara, Italy

来源：

SCIENTIFIC REPORTS | 2019年 / 9卷 / 1期

基金：

欧盟地平线“2020”;

关键词：

NLRP3; INFLAMMASOME; ALZHEIMERS-DISEASE; SCAVENGER ACTIVITY; IL-1-BETA RELEASE; ACTIVATION; CALCIUM; CELLS; PATHOGENESIS; MACROPHAGES; PARTICLES;

D O I：

10.1038/s41598-019-42931-2

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Previous data from our laboratory show that expression of the P2X7 receptor (P2X7R) is needed for amyloid beta(A beta)-stimulated microglia activation and IL-1 beta release in vitro and in vivo. We also showed that A beta-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 beta(A beta)-dependent NLRP3 inflammasome expression and function, and on mitochondrial energy metabolism. Our data show that in microglia A beta causes P2X7R-dependent a) NF kappa B 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 A beta, points to the mitochondria as a crucial target, and underlines the permissive role of the P2X7R.

引用

页数：15

共 47 条

[1] Basal activation of the P2X7 ATP receptor elevates mitochondrial calcium and potential, increases cellular ATP levels, and promotes serum-independent growth [J].