Mutant SOD1^G93A microglia are more neurotoxic relative to wild-type microglia

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.