Mutant SOD1G93A microglia are more neurotoxic relative to wild-type microglia

被引:132
作者
Xiao, Qin
Zhao, Weihua
Beers, David R.
Yen, Albert A.
Xie, Wenjie
Henkel, Jenny S.
Appel, Stanley H. [1 ]
机构
[1] Methodist Neurol Inst, Dept Neurol, Houston, TX USA
[2] Shanghai Jiao Tong Univ, Sch Med, Ruijin Hosp, Dept Neurol, Shanghai 200030, Peoples R China
[3] Shanghai Jiao Tong Univ, Sch Med, Ruijin Hosp, Inst Neurol, Shanghai 200030, Peoples R China
[4] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA
关键词
amyotrophic lateral sclerosis; insulin-like growth factor-1; microglia; motoneuron; nitric oxide; superoxide; AMYOTROPHIC-LATERAL-SCLEROSIS; PERINATAL HYPOXIA-ISCHEMIA; TRANSGENIC MOUSE MODEL; NITRIC-OXIDE SYNTHASE; MOTOR-NEURON DEATH; GROWTH-FACTOR-I; ACTIVATED MICROGLIA; MOTONEURON DISEASE; EXTEND SURVIVAL; FAMILIAL ALS;
D O I
10.1111/j.1471-4159.2007.04677.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:2008 / 2019
页数:12
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