Impaired recruitment of neuroprotective microglia and T cells during acute neuronal injury coincides with increased neuronal vulnerability in an amyotrophic lateral sclerosis model
- 作者：Mami Fukunaga Kawamura fmami@neuro.med.kyushu-u.ac.jp ; Ryo Yamasaki ryoya@neuro.med.kyushu-u.ac.jp ; Nobutoshi Kawamura nobutosi@neuro.med.kyushu-u.ac.jp ; Takahisa Tateishi tatetaka@neuro.med.kyushu-u.ac.jp ; Yuko Nagara ynagara@neuro.med.kyushu-u.ac.jp ; Takuya Matsushita matusita@neuro.med.kyushu-u.ac.jp ; Yasumasa Ohyagi ohyagi@neuro.med.kyushu-u.ac.jp ; Jun-ichi Kira ; kira@neuro.med.kyushu-u.ac.jp
- 关键词：ALS ; amyotrophic lateral sclerosis ; GAPDH ; glyceraldehyde-3-phosphate dehydrogenase ; GDNF ; glial cell line-derived neurotrophic factor ; Iba1 ; ionized calcium-binding adaptor molecule 1 ; IGF-1 ; insulin-like growth factor 1 ; iNOS ; inducible nitric oxide syn
- 刊名：Experimental Neurology
- 出版年：2012
- 期刊代码：78_00144886
- 类别：neu
- 出版时间：April, 2012
- 卷：234
- 期：2
- 页码：437-445
- 文件大小：2540 K
摘要
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.