ATP released from β-amyloid-stimulated microglia induces reactive oxygen species production in an autocrine fashion
ATP released from β-amyloid-stimulated microglia induces reactive oxygen species production in an autocrine fashion
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DOI：
10.1038/emm.2007.89
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发表时间：
2007-12-31
影响因子：
12.8
通讯作者：
Lee, Yong'Beorn
中科院分区：
文献类型：
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作者：
Kim, Soo Yoon;Moon, Ju Hyun;Lee, Yong'Beorn
目前的研究表明，纤维β -淀粉样肽（fA β(1-42)）诱导ATP释放，进而通过P2X(7)受体（P2X(7)R）激活NADPH氧化酶。fA β(1-42)处理的小胶质细胞中活性氧（ROS）的产生似乎需要来自细胞外来源的Ca2+内流，因为在缺乏细胞外Ca2+的情况下，ROS的产生被废除以控制水平。考虑到之前在小胶质细胞中观察到Ca2+内流通过P2X(7)R产生超氧化物，我们假设fA β刺激的小胶质细胞中ROS的产生可能是由小胶质细胞释放的ATP介导的。因此，我们研究了fAp（1-42）诱导的Ca2+内流是否通过P2X(7)R激活介导。在一系列实验中，我们发现用P2X(7)R拮抗剂吡哆醛-磷酸-6-偶氮苯基-2′，4′-二磺酸盐（100 μ M）或氧化ATP （100 μ M）预处理小胶质细胞可以抑制fA β诱导的Ca2+内流，并将ROS生成降低到基础水平。此外，观察到fA β(1-42)刺激的小胶质细胞的ATP外排，并且apyrase处理减少了ROS的产生。这些发现提供了确凿的证据，证明fA β刺激的小胶质细胞中ROS的产生是由小胶质细胞自分泌释放的ATP调节的。
Present study demonstrated that fibrillar beta-amyloid peptide (fA beta(1-42)) induced ATP release, which in turn activated NADPH oxidase via the P2X(7) receptor (P2X(7)R). Reactive oxygen species (ROS) production in fA beta(1-42)-treated microglia appeared to require Ca2+ influx from extracellular sources, because ROS generation was abolished to control levels in the absence of extracellular Ca2+. Considering previous observation of superoxide generation by Ca2+ influx through P2X(7)R in microglia, we hypothesized that ROS production in fA beta-stimulated microglia might be mediated by ATP released from the microglia. We therefore examined whether fAp(1-42)-induced Ca2+ influx was mediated through P2X(7)R activation. In serial experiments, we found that microglial pretreatment with the P2X(7)R antagonists Pyridoxal-phosphate-6-azophenyl-2',4'-disulfonate (100 mu M) or oxidized ATP (100 mu M) inhibited fA beta-induced Ca2+ influx and reduced ROS generation to basal levels. Furthermore, ATP efflux from fA beta(1-42)-stimulated microglia was observed, and apyrase treatment decreased the generation of ROS. These findings provide conclusive evidence that fA beta-stimulated ROS generation in microglial cells is regulated by ATP released from the microglia in an autocrine manner.