Abstract
BackgroundComponents 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 hSOD1G93A mice during defined disease stages.MethodshSOD1G93A 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 hSOD1G93A and wild-type mice were analysed using a two-tailed t-test at each stage of disease progression.ResultsWe 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 hSOD1G93A 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.ConclusionsThese results indicate that local complement activation and increased expression of CD88 may contribute to motor neuron death and ALS pathology in the hSOD1G93A mouse. Hence, reducing complement-induced inflammation could be an important therapeutic strategy to treat ALS.
Highlights
Components of the innate immune complement system have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS); a comprehensive examination of complement expression in this disease has not been performed
Mice. (A, B) Data expressed as mean ± standard error of the mean (n = 6 mice/group; *P
Semiquantitative densitometry analyses of these bands with respect to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) loading controls (Figure 5B, lower panel) revealed increased CD88 protein in the lumbar spinal cord mice. (A, B) Data expressed as mean ± standard error of the mean (n = 6 mice/group; *P
Summary
Components of the innate immune complement system have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS); a comprehensive examination of complement expression in this disease has not been performed. Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder characterised by selective loss of upper motor neurons within the motor cortex, and of αmotor neurons of the spinal cord and brainstem [1] This results in symptoms of muscle weakness and atrophy of skeletal muscles, leading to paralysis and eventual death due to failure of respiratory muscles [2]. Our group has shown that chronic administration of a specific CD88 antagonist in hSOD1G93A transgenic rats delayed the onset of motor symptoms and increased survival compared with untreated animals [11] Overall, these studies indicate that overactivation of the complement system and increased C5a-CD88 signalling contribute to the progression of disease in these animal models of ALS
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