Therapeutic blockade of HMGB1 reduces early motor deficits, but not survival in the SOD1G93A mouse model of amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing neurodegenerative disease without effective treatment. The receptor for advanced glycation end products (RAGE) and the toll-like receptor (TLR) system are major components of the innate immune system, which have been implicated in ALS pathology. Extracellularly released high-mobility group box 1 (HMGB1) is a pleiotropic danger-associated molecular pattern (DAMP), and is an endogenous ligand for both RAGE and TLR4. METHODS: The present study examined the effect of HMGB1 inhibition on disease progression in the preclinical SOD1G93A transgenic mouse model of ALS using a potent anti-HMGB1 antibody (2G7), which targets the extracellular DAMP form of HMGB1. RESULTS: We found that chronic intraperitoneal dosing of the anti-HMGB1 antibody to SOD1G93A mice transiently improved hind-limb grip strength early in the disease, but did not extend survival. Anti-HMGB1 treatment also reduced tumour necrosis factor α and complement C5a receptor 1 gene expression in the spinal cord, but did not affect overall glial activation. CONCLUSIONS: In summary, our results indicate that therapeutic targeting of an extracellular DAMP, HMGB1, improves early motor dysfunction, but overall has limited efficacy in the SOD1G93A mouse model of ALS.

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

BACKGROUND: 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-43Q331K mice during different disease ages. METHODS: Non-transgenic, TDP-43WT and TDP-43Q331K 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. RESULTS: Altered levels of several major complement factors, including C5a, in the spinal cord and tibialis anterior muscle of TDP-43Q331K mice were observed as disease progressed, suggesting overall increased complement activation in TDP-43Q331K 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. CONCLUSIONS: 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-43Q331K mouse ALS model. This further validates C5aR1 as a potential therapeutic target for ALS.