Department of Physiological, Biochemical and Cell Science, University of Sassari, Sassari, Italy.
PLoS One. 2011 Mar 18;6(3):e17187. doi: 10.1371/journal.pone.0017187.
Motor neuron death in amyotrophic lateral sclerosis (ALS) is considered a "non-cell autonomous" process, with astrocytes playing a critical role in disease progression. Glial cells are activated early in transgenic mice expressing mutant SOD1, suggesting that neuroinflammation has a relevant role in the cascade of events that trigger the death of motor neurons. An inflammatory cascade including COX2 expression, secretion of cytokines and release of NO from astrocytes may descend from activation of a NF-κB-mediated pathway observed in astrocytes from ALS patients and in experimental models. We have attempted rescue of transgenic mutant SOD1 mice through the inhibition of the NF-κB pathway selectively in astrocytes. Here we show that despite efficient inhibition of this major pathway, double transgenic mice expressing the mutant SOD1(G93A) ubiquitously and the dominant negative form of IκBα (IκBαAA) in astrocytes under control of the GFAP promoter show no benefit in terms of onset and progression of disease. Our data indicate that motor neuron death in ALS cannot be prevented by inhibition of a single inflammatory pathway because alternative pathways are activated in the presence of a persistent toxic stimulus.
肌萎缩侧索硬化症（ALS）中的运动神经元死亡被认为是一种“非细胞自主”过程，星形胶质细胞在疾病进展中起着关键作用。在表达突变 SOD1 的转基因小鼠中，神经胶质细胞很早就被激活，这表明神经炎症在引发运动神经元死亡的级联反应中具有重要作用。包括 COX2 表达、细胞因子分泌和 NO 从星形胶质细胞释放的炎症级联反应可能源于 ALS 患者和实验模型中的星形胶质细胞中观察到的 NF-κB 介导途径的激活。我们试图通过选择性抑制星形胶质细胞中的 NF-κB 途径来挽救表达突变 SOD1 的转基因小鼠。在这里，我们表明，尽管这条主要途径得到了有效的抑制，但在 GFAP 启动子的控制下，在星形胶质细胞中广泛表达突变 SOD1(G93A)和显性负形式的 IκBα（IκBαAA）的双转基因小鼠在疾病的发病和进展方面没有任何益处。我们的数据表明，由于存在持续的毒性刺激，单一炎症途径的抑制不能预防 ALS 中的运动神经元死亡，因为会激活替代途径。
