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首页> 外文期刊>The European Journal of Neuroscience >ERK activation and nuclear translocation in amyloid-beta peptide- and iron-stressed neuronal cell cultures.
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ERK activation and nuclear translocation in amyloid-beta peptide- and iron-stressed neuronal cell cultures.

机译：淀粉样蛋白β肽和铁应激神经元细胞培养物中的ERK激活和核易位。

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Oxidative stress in the human brain has been strongly implicated as the cause of neuronal cell losses in Alzheimer's disease patients, but the exact mechanism still remains unknown. In this report several oxidative stress parameters and an associated signalling transduction cascade predating neuronal cell death in cultures treated with the oxidative stressors Fe2+ (5 micro m) and the amyloid beta (Abeta1-40) peptide (5 micro m) were studied. Production of reactive oxygen species as detected by dichlorofluorescein staining was apparent within 5 min in the presence of both agents. Lipid peroxide content increased by approximately 10-fold after 2 h, while mitochondrial activity was impaired by 40% after 6 h. Caspase-3 activity was elevated 5-6 fold, all indicative of oxidative cell stress. The combined presence of Abeta1-40 and Fe2+ resulted in a rapid (5 min) ERK activation followed by a decline by 30 min and a second activation that continued up to 24 h when nuclear translocation was noticed. Neither treatment with Fe2+ nor that with Abeta1-40 alone caused similar changes. Addition of either deferroxamine (DFe, 25 micro m), catalase (0.4 mg/mL) or N-acetyl cysteine (0.5 mm) - the last two known as suppressants of oxidative stress - attenuated ERK activation and nuclear translocation. The mitogen-activated protein/ERK kinase (MEK) inhibitor U0126 blocked ERK and caspase 3 activation, suppressed ERK translocation and reduced the number of apoptotic cells, suggesting a central role for the ERK signalling cascade in Abeta1-40 plus Fe2+ (Abeta1-40/Fe2+) -induced apoptotic death. The full peptide Abeta1-42 was very effective at 0.5 micro m while the inverse peptide Abeta40-1 at 5 micro m was ineffective. The acetyl-amyloid-beta protein amide fragment 15-20 (V-pep) known to be an Abeta aggregation inhibitor, prevented Abeta1-40/Fe2+-induced toxicity. These findings indicate that metal ions chelators and antioxidants suppress the Abeta1-40/Fe2+-induced oxidative stress cascade and may be beneficial in reducing the severity of Alzheimer's disease.
机译：人脑中的氧化应激已被认为是阿尔茨海默氏病患者神经元细胞丢失的原因，但确切的机制仍然未知。在此报告中，研究了在用氧化应激因子Fe2 +（5微米）和淀粉样β（Abeta1-40）肽（5微米）处理的培养物中的几个氧化应激参数和相关的信号传导级联反应，预测神经元细胞死亡。在两种试剂均存在的情况下，在5分钟内通过二氯荧光素染色检测到了活性氧的产生。 2小时后脂质过氧化物的含量增加了约10倍，而6小时后线粒体的活性却降低了40％。 Caspase-3活性提高了5-6倍，均表明氧化细胞应激。 Abeta1-40和Fe2 +的共同存在导致快速（5分钟）ERK活化，随后下降30分钟，第二次活化在观察到核易位时持续长达24小时。用Fe2 +或单独使用Abeta1-40都不会引起类似的变化。加入后铁胺（DFe，25微米），过氧化氢酶（0.4 mg / mL）或N-乙酰半胱氨酸（0.5 mm）-后两种被称为氧化应激抑制剂-减弱ERK活化和核易位。有丝分裂原激活的蛋白/ ERK激酶（MEK）抑制剂U0126阻断ERK和caspase 3的激活，抑制ERK的转运并减少凋亡细胞的数量，这表明ERK信号级联在Abeta1-40和Fe2 +（Abeta1-40 / Fe2 +）诱导的细胞凋亡死亡。完整的肽Abeta1-42在0.5微米处非常有效，而反向肽Abeta40-1在5微米处无效。已知是Abeta聚集抑制剂的乙酰淀粉样β蛋白酰胺片段15-20（V-pep）可以防止Abeta1-40 / Fe2 +诱导的毒性。这些发现表明，金属离子螯合剂和抗氧化剂可以抑制Abeta1-40 / Fe2 +诱导的氧化应激级联反应，并且可能有助于降低阿尔茨海默氏病的严重程度。

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