Lezoualc'h F, Sagara Y, Holsboer F, Behl C
Max-Planck-Institute of Psychiatry, 80804 Munich, Germany.
J Neurosci. 1998 May 1;18(9):3224-32. doi: 10.1523/JNEUROSCI.18-09-03224.1998.
Selected clones of the sympathetic precursor-like cell line PC12 (rCl8) are resistant to oxidative cell death induced by the Alzheimer's disease-associated amyloid beta protein (Abeta) and hydrogen peroxide (H2O2). Here, we show that the transcriptional activity and DNA binding activity of the redox-sensitive transcription factor NF-kappaB and its nuclear expression are constitutively increased in rCl8 cells compared with their nonresistant parental PC12 cell (PC12p) counterpart. Suppression of the transcriptional activity of NF-kappaB in rCl8 cells with the synthetic glucocorticoid dexamethasone or by direct overexpression of a super-repressor mutant form of IkappaBalpha, a specific inhibitor of NF-kappaB, reversed the oxidative stress resistance phenotype of these cells and ultimately led to increased cell death after the challenge with H2O2. Dexamethasone treatment also caused an increase in the protein level of IkappaBalpha. Our data show that an increased baseline of NF-kappaB activity may mediate the resistance of these cells of neuronal origin to oxidative stress. Therefore, the presented model may help to identify possible neuronal target genes of NF-kappaB and to further elucidate the molecular basis of the differential sensitivity of neurons in neurodegenerative conditions associated with an increased oxidative burden, such as in Alzheimer's disease.
交感神经前体样细胞系PC12（rCl8）的选定克隆对阿尔茨海默病相关淀粉样β蛋白（Aβ）和过氧化氢（H2O2）诱导的氧化性细胞死亡具有抗性。在此，我们表明，与非抗性亲代PC12细胞（PC12p）相比，氧化还原敏感转录因子NF-κB的转录活性、DNA结合活性及其核表达在rCl8细胞中组成性增加。用合成糖皮质激素地塞米松或通过直接过表达NF-κB的特异性抑制剂IkappaBalpha的超阻遏突变体形式来抑制rCl8细胞中NF-κB的转录活性，可逆转这些细胞的氧化应激抗性表型，并最终导致在用H2O2刺激后细胞死亡增加。地塞米松处理还导致IkappaBalpha蛋白水平升高。我们的数据表明，NF-κB活性的基线升高可能介导了这些神经源性细胞对氧化应激的抗性。因此，所提出的模型可能有助于识别NF-κB可能的神经元靶基因，并进一步阐明在与氧化负担增加相关的神经退行性疾病（如阿尔茨海默病）中神经元敏感性差异的分子基础。
