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Primary Cultures of Rat Astrocytes and Microglia and Their Use in the Study of Amyotrophic Lateral Sclerosis
Published on: June 23, 2022
Mutant SOD1(G93A) microglia are more neurotoxic relative to wild-type microglia
Qin Xiao1, Weihua Zhao1, David R Beers1
1Department of Neurology, Methodist Neurological Institute, Houston, Texas, USADepartment of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, ChinaDepartment of Neurology, Baylor College of Medicine, Houston, Texas, USA.
Abstract:
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.
Insights
Microglia with mutant SOD1 (mSOD1(G93A)) are more neurotoxic, causing increased motoneuron death in amyotrophic lateral sclerosis models. This heightened toxicity is linked to elevated nitric oxide release from these specific microglia.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Microglia, the immune cells of the central nervous system, play a critical role in neuroinflammation.
- Over-expression of mutant human superoxide dismutase (mSOD1(G93A)) is implicated in familial amyotrophic lateral sclerosis (ALS).
- The specific contribution of microglia expressing mSOD1(G93A) to motoneuron degeneration in ALS remains under investigation.
Purpose of the Study:
- To compare the neurotoxic potential of wild-type microglia, mSOD1(G93A) microglia, and microglia over-expressing wild-type human SOD1.
- To investigate the impact of lipopolysaccharide (LPS) stimulation on microglial function and neurotoxicity.
- To elucidate the mechanisms underlying microglia-mediated motoneuron injury in the context of ALS.
Main Methods:
- Primary cultures of microglia and motoneurons were utilized.
- Microglia were genetically modified to over-express either wild-type SOD1 or mSOD1(G93A).
- Co-cultures of microglia and motoneurons were established and treated with lipopolysaccharide (LPS).
- Measurements included nitric oxide, superoxide, insulin-like growth factor-1 (IGF-1) release, motoneuron survival, and neurite outgrowth.
Main Results:
- Activated mSOD1(G93A) microglia released significantly more nitric oxide and superoxide, and less IGF-1 compared to wild-type microglia.
- In co-cultures, mSOD1(G93A) microglia induced greater motoneuron death and reduced neurite length and number.
- Motoneuron injury was more pronounced with mSOD1(G93A) microglia than with microglia over-expressing wild-type SOD1.
- Motoneuron survival was inversely correlated with nitric oxide (nitrate + nitrite) levels in mSOD1(G93A) microglia co-cultures.
Conclusions:
- Microglia expressing mSOD1(G93A) exhibit enhanced neurotoxicity compared to wild-type microglia.
- Nitric oxide release from mSOD1(G93A) microglia is a key mediator of motoneuron injury in this ALS model.
- These findings highlight the detrimental role of specific microglial genotypes in ALS pathogenesis.
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