Medical Science and Engineering Research Center for Bioreaction to Reactive Oxygen Species, Biomedical Science Institute (BK-21), Kyung Hee University, Seoul 134-727, Korea.
Free Radic Biol Med. 2011 Aug 15;51(4):905-20. doi: 10.1016/j.freeradbiomed.2011.05.036. Epub 2011 Jun 2.
Accumulated amyloid-β (Aβ) is a well-known cause of neuronal apoptosis in Alzheimer disease and functions in part by generating oxidative stress. Our previous work suggested that cyclophilin B (CypB) protects against endoplasmic reticulum (ER) stress. Therefore, in this study we examined the ability of CypB to protect against Aβ toxicity. CypB is present in the neurons of rat and mouse brains, and treating neural cells with Aβ(25-35) mediates apoptotic cell death. Aβ(25-35)-induced neuronal toxicity was inhibited by the overexpression of CypB as measured by cell viability, apoptotic morphology, sub-G1 cell population, intracellular reactive oxygen species accumulation, activated caspase-3, PARP cleavage, Bcl-2 proteins, mitogen-activated protein kinase (MAPK) activation, and phosphoinositide 3-kinase (PI-3-K) activation. CypB/R95A PPIase mutants did not reduce Aβ(25-35) toxicity. We showed that Aβ(25-35)-induced apoptosis is more severe in a CypB knockdown model, confirming that CypB protects against Aβ(25-35)-induced toxicity. Consequently, these findings suggest that CypB may protect against Aβ toxicity by its antioxidant properties, by regulating MAPK and PI-3-K signaling, and through the ER stress pathway.
淀粉样蛋白-β (Aβ) 的积累是阿尔茨海默病中神经元凋亡的已知原因，部分通过产生氧化应激起作用。我们之前的工作表明亲环素 B (CypB) 可抵抗内质网 (ER) 应激。因此，在这项研究中，我们研究了 CypB 抵抗 Aβ 毒性的能力。CypB 存在于大鼠和小鼠大脑的神经元中，用 Aβ(25-35) 处理神经细胞可介导细胞凋亡。通过细胞活力、凋亡形态、亚 G1 细胞群、细胞内活性氧积累、激活的 caspase-3、PARP 切割、Bcl-2 蛋白、丝裂原激活蛋白激酶 (MAPK) 激活和磷酸肌醇 3-激酶 (PI-3-K) 激活来衡量，CypB 的过表达可抑制 Aβ(25-35) 诱导的神经元毒性。CypB/R95A PPIase 突变体不能降低 Aβ(25-35) 的毒性。我们表明，在 CypB 敲低模型中，Aβ(25-35) 诱导的凋亡更为严重，证实 CypB 可抵抗 Aβ(25-35) 诱导的毒性。因此，这些发现表明 CypB 可能通过其抗氧化特性、调节 MAPK 和 PI-3-K 信号以及通过内质网应激途径来保护免受 Aβ 毒性。
