Journal
MOLECULAR NEUROBIOLOGY
Volume 57, Issue 10, Pages 4143-4155Publisher
SPRINGER
DOI: 10.1007/s12035-020-02019-9
Keywords
HMGB1; DAMP; Neuroinflammation; Innate immune system
Categories
Funding
- Motor Neuron Disease Research Institute of Australia (MNDRIA) Postdoctoral Fellowship [PDF1604]
- National Health and Medical Research Council (NHMRC) [APP1082271]
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Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing motor neuron degenerative disease that is without effective treatment. The receptor for advanced glycation end products (RAGE) is a major component of the innate immune system that has been implicated in ALS pathogenesis. However, the contribution of RAGE signalling to the neuroinflammation that underlies ALS neurodegeneration remains unknown. The present study therefore generated SOD1(G93A) mice lacking RAGE and compared them with SOD1(G93A) transgenic ALS mice in respect to disease progression (i.e. body weight, survival and muscle strength), neuroinflammation and denervation markers in the spinal cord and tibialis anterior muscle. We found that complete absence of RAGE signalling exerted a protective effect on SOD1(G93A) pathology, slowing disease progression and significantly extending survival by similar to 3 weeks and improving motor function (rotarod and grip strength). This was associated with reduced microgliosis, cytokines, innate immune factors (complement, TLRs, inflammasomes), and oxidative stress in the spinal cord, and a reduction of denervation markers in the tibialis anterior muscle. We also documented that RAGE mRNA expression was significantly increased in the spinal cord and muscles of preclinical SOD1 and TDP43 models of ALS, supporting a widespread involvement for RAGE in ALS pathology. In summary, our results indicate that RAGE signalling drives neuroinflammation and contributes to neurodegeneration in ALS and highlights RAGE as a potential immune therapeutic target for ALS.
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