Complement components are upregulated and correlate with disease progression in the TDP-43^Q331K mouse model of...

Components of the innate immune complement system have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) specifically using hSOD1 transgenic animals; however, a comprehensive examination of complement expression in other transgenic ALS models has not been performed. This study therefore aimed to determine the expression of several key complement components and regulators in the lumbar spinal cord and tibialis anterior muscle of TDP-43^Q331K mice during different disease ages.

Non-transgenic, TDP-43^WT and TDP-43^Q331K mice were examined at three different ages of disease progression. Expression of complement components and their regulators were examined using real-time quantitative PCR and enzyme-linked immunosorbent assay. Localisation of terminal complement component receptor C5aR1 within the lumbar spinal cord was also investigated using immunohistochemistry.

Altered levels of several major complement factors, including C5a, in the spinal cord and tibialis anterior muscle of TDP-43^Q331K mice were observed as disease progressed, suggesting overall increased complement activation in TDP-43^Q331K mice. C5aR1 increased during disease progression, with immuno-localisation demonstrating expression on motor neurons and expression on microglia surrounding the regions of motor neuron death. There was a strong negative linear relationship between spinal cord C1qB, C3 and C5aR1 mRNA levels with hind-limb grip strength.

These results indicate that similar to SOD1 transgenic animals, local complement activation and increased expression of C5aR1 may contribute to motor neuron death and neuromuscular junction denervation in the TDP-43^Q331K mouse ALS model. This further validates C5aR1 as a potential therapeutic target for ALS.