Department Neurology, Neurological Institute, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan.
Exp Neurol. 2012 Apr;234(2):437-45. doi: 10.1016/j.expneurol.2012.01.015. Epub 2012 Jan 24.
Non-cell-autonomous motor neuronal death is suggested in a mutant Cu/Zn superoxide dismutase 1 (mSOD1)-mediated amyotrophic lateral sclerosis (ALS) model, in which microglia and T cells play significant roles in disease progression. However, it remains unknown whether these cells are toxic or protective. The present study aimed to clarify the developmental age-related alterations of neuronal, glial and T cell responses to acute neuron injury in non-transgenic (N-Tg) mice, and the in vivo effects of mSOD1 on these changes by studying N-Tg and mSOD1-Tg mice subjected to unilateral hypoglossal nerve axotomy at young (8 weeks) and adult (17 weeks) ages. Adult N-Tg mice showed increased neuronal viability on day 21 after axotomy and trends toward increased numbers of recruited microglia on day 3 and T cells on day 7, in the hypoglossal nucleus, compared with young N-Tg mice. Quantitative comparisons between mSOD1-Tg and N-Tg mice at the same ages, on day 3 after axotomy, showed that microglial recruitment was significantly lower in mSOD1-Tg mice than in 17-week-old N-Tg mice (the disease progression stage), but the same difference was not seen in 8-week-old mice (the presymptomatic stage), despite good preservation of hypoglossal neurons. Infiltration of CD3-positive T cells, mostly CD4-positive, on day 7 and the viability rate of hypoglossal neurons on the operated side compared with the contralateral side on day 21 were significantly decreased in mSOD1-Tg mice compared with N-Tg mice aged 17 weeks, but the same difference was not seen in mice aged 8 weeks. On day 3 after axotomy, expression levels of IGF-1 mRNA in the operated hypoglossal nucleus were significantly lower in mSOD1-Tg mice than N-Tg mice at 17 weeks of age. The observation that depressed microglial and T cell responses and expression of neurotrophic factors coincided with reduced neuronal viability in adult mSOD1-Tg mice suggests that diminished neuroprotective functions of mSOD1 microglia and T cells may contribute to exaggerated neuronal death.
非细胞自主运动神经元死亡在突变铜/锌超氧化物歧化酶 1（mSOD1）介导的肌萎缩侧索硬化症（ALS）模型中被提出，其中小胶质细胞和 T 细胞在疾病进展中起着重要作用。然而，这些细胞是有毒的还是有保护作用尚不清楚。本研究旨在阐明非转基因（N-Tg）小鼠急性神经元损伤后神经元、神经胶质和 T 细胞反应的发育年龄相关性变化，以及通过研究接受单侧舌下神经轴突切断术的年轻（8 周）和成年（17 周）N-Tg 和 mSOD1-Tg 小鼠，mSOD1 对这些变化的体内影响。与年轻的 N-Tg 小鼠相比，成年 N-Tg 小鼠在舌下神经核中，损伤后第 21 天神经元存活率增加，损伤后第 3 天和第 7 天募集的小胶质细胞和 T 细胞数量呈增加趋势。在同一年龄，损伤后第 3 天 mSOD1-Tg 和 N-Tg 小鼠之间的定量比较显示，mSOD1-Tg 小鼠的小胶质细胞募集明显低于 17 周龄 N-Tg 小鼠（疾病进展阶段），但在 8 周龄小鼠中未出现这种差异（疾病前期），尽管舌下神经神经元保存良好。与未受损的对侧相比，损伤后第 7 天 CD3 阳性 T 细胞（主要为 CD4 阳性）的浸润以及手术侧舌下神经元的存活率在 mSOD1-Tg 小鼠中明显降低，而在 17 周龄 N-Tg 小鼠中则无此差异。与 17 周龄的 N-Tg 小鼠相比，损伤后第 3 天 mSOD1-Tg 小鼠手术侧舌下神经核中 IGF-1 mRNA 的表达水平明显降低。在成年 mSOD1-Tg 小鼠中，观察到小胶质细胞和 T 细胞反应以及神经营养因子表达的抑制与神经元存活率降低相一致，这表明 mSOD1 小胶质细胞和 T 细胞的神经保护功能减弱可能导致神经元死亡加剧。
