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A Quick Phenotypic Neurological Scoring System for Evaluating Disease Progression in the SOD1-G93A Mouse Model of ALS
Published on: October 6, 2015
Dysregulation of the complement cascade in the hSOD1G93A transgenic mouse model of amyotrophic lateral sclerosis
John D Lee1, Nur A Kamaruzaman, Jenny N T Fung
1School of Biomedical Sciences, University of Queensland, Brisbane, St Lucia QLD 4072, Australia. t.woodruff@uq.edu.au.
Insights
Complement activation increases and regulators decrease in amyotrophic lateral sclerosis (ALS) mouse models. Increased CD88 expression on motor neurons and microglia suggests a role in motor neuron death, offering potential therapeutic targets.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- The innate immune complement system is implicated in amyotrophic lateral sclerosis (ALS) pathogenesis.
- Comprehensive analysis of complement expression in ALS has been lacking.
- This study investigates complement components and regulators in a mouse model of ALS.
Purpose of the Study:
- To determine the expression of key complement components (C1qB, C4, factor B, C3/C3b, C5, CD88) and regulators (CD55, CD59a) in the lumbar spinal cord of hSOD1(G93A) mice.
- To examine these changes across defined stages of disease progression.
- To correlate complement system alterations with ALS pathology.
Main Methods:
- Utilized hSOD1(G93A) and wild-type mice at four distinct ages.
- Assessed mRNA and protein expression via quantitative PCR, western blotting, and ELISA.
- Investigated complement component localization using immunohistochemistry.
Main Results:
- Observed increased expression of early complement factors and decreased complement regulators as ALS progressed in hSOD1(G93A) mice.
- Detected elevated CD88 expression on motor neurons and microglia, particularly near dying motor neurons.
- Results suggest enhanced classical or alternative complement pathway activation.
Conclusions:
- Local complement activation and elevated CD88 expression may contribute to motor neuron death in ALS.
- Targeting complement-induced inflammation presents a potential therapeutic strategy for ALS treatment.
Background:
Components of the innate immune complement system have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS); however, a comprehensive examination of complement expression in this disease has not been performed. This study therefore aimed to determine the expression of complement components (C1qB, C4, factor B, C3/C3b, C5 and CD88) and regulators (CD55 and CD59a) in the lumbar spinal cord of hSOD1(G93A) mice during defined disease stages.
Methods:
hSOD1(G93A) and wild-type mice were examined at four different ages of disease progression. mRNA and protein expression of complement components and regulators were examined using quantitative PCR, western blotting and ELISA. Localisation of complement components within lumbar spinal cord was investigated using immunohistochemistry. Statistical differences between hSOD1(G93A) and wild-type mice were analysed using a two-tailed t-test at each stage of disease progression.
Results:
We found several early complement factors increased as disease progressed, whilst complement regulators decreased; suggesting overall increased complement activation through the classical or alternative pathways in hSOD1(G93A) mice. CD88 was also increased during disease progression, with immunolocalisation demonstrating expression on motor neurons and increasing expression on microglia surrounding the regions of motor neuron death.
Conclusions:
These results indicate that local complement activation and increased expression of CD88 may contribute to motor neuron death and ALS pathology in the hSOD1(G93A) mouse. Hence, reducing complement-induced inflammation could be an important therapeutic strategy to treat ALS.
