Poly(ADP-ribose) polymerase-1 regulates microglia mediated decrease of endothelial tight junction integrity
Poly(ADP-ribose) polymerase-1 regulates microglia mediated decrease of endothelial tight junction integrity
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DOI：
10.1016/j.neuint.2017.04.014
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发表时间：
2017-09-01
影响因子：
4.2
通讯作者：
Kauppinen, Tiina M.
中科院分区：
文献类型：
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作者：
Mehrabadi, Abbas Rezaeian;Korolainen, Minna A.;Kauppinen, Tiina M.
除了神经元损伤之外，阿尔茨海默病病理学还包括反应性神经胶质增生和降低的血脑屏障（BBB）完整性。小胶质细胞与BBB密切相关，并且在AD病理学上，小胶质细胞的促炎反应可能导致BBB损伤。为了研究小胶质细胞是否可以直接影响BBB完整性，评估了淀粉样蛋白β（A β）刺激的原代鼠小胶质细胞对共培养的小鼠脑内皮细胞（bEnd 3）和鼠星形胶质细胞培养物的影响。我们还评估了通过抑制/消除聚（ADP-核糖）聚合酶-1（PARP-1）来调节小胶质细胞表型是否可以逆转小胶质细胞对这些BBB形成细胞的影响。在共培养的内皮细胞中，未受刺激的小胶质细胞促进了紧密连接蛋白（TJPs）、封闭小带-1（ZO-1）和occludin的表达，而A β刺激的小胶质细胞减少了ZO-1和occludin的内皮表达。与小胶质细胞共培养的星形胶质细胞显示胶质细胞酸性蛋白（GFAP）表达升高，如果用AO刺激小胶质细胞，则其表达进一步增加。A β诱导小胶质细胞释放一氧化氮（NO）和肿瘤坏死因子α（TNF α），导致TJPs的内皮表达减少和细胞旁通透性增加。小胶质细胞PARP-1抑制减弱了这些A β诱导的事件。这些发现表明，PARP-1介导的小胶质细胞反应（NO和TNF α）可通过促进TJP降解、增加内皮细胞通透性和诱导星形胶质细胞增生直接降低BBB完整性。PARP-1作为小胶质细胞表型的调节剂，可以预防小胶质细胞BBB损伤事件，因此是潜在的治疗靶点。(C)2017爱思唯尔有限公司版权所有
Alzheimer's disease pathology includes, beside neuronal damage, reactive gliosis and reduced blood brain barrier (BBB) integrity. Microglia are intimately associated with the BBB and upon AD pathology, pro-inflammatory responses of microglia could contribute to BBB damage. To study whether microglia can directly affect BBB integrity, the effects of amyloid beta (A beta-stimulated primary murine microglia on co-cultured mouse brain endothelial cells (bEnd3) and murine astrocyte cultures were assessed. We also assessed whether microglial phenotype modulation via poly(ADP-ribose) polymerase-1 (PARP-1) inhibition/ablation can reverse microglial impact on these BBB forming cells.Unstimulated microglia promoted expression of tight junction proteins (TJPs), zonula ocluden-1 (ZO-1) and occludin in co-cultured endothelia cells, whereas A beta-stimulated microglia reduced endothelial expression of ZO-1 and occludin. Astrocytes co-cultured with microglia showed elevated glial fibrillary acidic protein (GFAP) expression, which was further increased if microglia had been stimulated with AO. A beta induced microglial release of nitric oxide (NO) and tumour necrosis factor alpha (TNF alpha), which resulted in reduced endothelial expression of TJPs and increased paracellular permeability. Microglial PARP-1 inhibition attenuated these A beta-induced events. These findings demonstrate that PARP-1 mediated microglial responses (NO and TNF alpha) can directly reduce BBB integrity by promoting TJP degradation, increasing endothelial cell permeability and inducing astrogliosis. PARP-1 as a modulator of microglial phenotype can prevent microglial BBB damaging events, and thus is a potential therapeutic target. (C) 2017 Elsevier Ltd. All rights reserved.