Mutant SOD1G93A microglia are more neurotoxic relative to wild-type microglia
Mutant SOD1G93A microglia are more neurotoxic relative to wild-type microglia
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DOI：
10.1111/j.1471-4159.2007.04677.x
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发表时间：
2007-09-01
影响因子：
4.7
通讯作者：
Appel, Stanley H.
中科院分区：
文献类型：
--
作者：
Xiao, Qin;Zhao, Weihua;Appel, Stanley H.
最近的研究表明，小胶质细胞过度表达突变的人超氧化物歧化酶（mSOD1(G93A)）可能导致家族性肌萎缩性侧索硬化症转基因小鼠模型中的运动神经元死亡。为了进一步评估野生型小胶质细胞、mSOD1（G93A）小胶质细胞和过表达野生型人SOD1的小胶质细胞的相对神经毒性，我们在存在和不存在脂多糖刺激的情况下使用了小胶质细胞和运动神经元的原代培养。在脂多糖激活后，mSOD1（G93A）小胶质细胞比野生型小胶质细胞释放更多的一氧化氮、更多的超氧化物和更少的胰岛素样生长因子-1。在小胶质细胞/运动神经元共培养中，与野生型小胶质细胞相比，mSOD1（G93A）小胶质细胞诱导更多的运动神经元死亡，神经突数量和长度减少。在小胶质细胞/运动神经元共培养中，突变型SOD1（G93A）小胶质细胞也比过表达野生型人SOD1的小胶质细胞诱导更多的运动神经元损伤。在mSOD1（G93A）共培养中，运动神经元存活与硝酸盐+亚硝酸盐浓度呈负相关，提示一氧化氮在小胶质细胞诱导的运动神经元损伤中起重要作用。因此，相对于野生型小胶质细胞，mSOD1（G93A）小胶质细胞比类似处理的野生型小胶质细胞具有更强的神经毒性，并诱导更多的运动神经元损伤。
Recent studies suggest that microglia over-expressing mutant human superoxide dismutase (mSOD1(G93A)) may contribute to motoneuron death in a transgenic mouse model of familial amyotrophic lateral sclerosis. To further assess the relative neurotoxicity of wild-type microglia, mSOD1(G93A) microglia, and microglia over-expressing wild-type human SOD1, we used primary cultures of microglia and motoneurons in the presence and absence of lipopolysaccharide stimulation. Following activation with lipopolysaccharide, mSOD1(G93A) microglia released more nitric oxide, more superoxide, and less insulin-like growth factor-1 than wild-type microglia. In microglia/motoneuron co-cultures, mSOD1(G93A) microglia induced more motoneuron death and decreased neurite numbers and length compared with wild-type microglia. Mutant SOD1(G93A) microglia also induced more motoneuron injury than microglia over-expressing wild-type human SOD1 in microglia/motoneuron co-cultures. Motoneuron survival was inversely correlated with nitrate + nitrite concentrations in mSOD1(G93A) co-cultures, suggesting the important role of nitric oxide in microglia-induced motoneuron injury. Thus, relative to wild-type microglia, mSOD1(G93A) microglia were more neurotoxic and induced more motoneuron injury than similarly treated wild-type microglia.