Absence of Receptor for Advanced Glycation End Product (RAGE) Reduces Inflammation and Extends Survival in the hSOD1 G93
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ORIGINAL ARTICLE
Absence of Receptor for Advanced Glycation End Product (RAGE) Reduces Inflammation and Extends Survival in the hSOD1G93A Mouse Model of Amyotrophic Lateral Sclerosis John D. Lee 1
&
Tanya S. McDonald 1
&
Jenny N. T. Fung 1
&
Trent M. Woodruff 1,2
Received: 1 May 2020 / Accepted: 8 July 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract 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 SOD1G93A mice lacking RAGE and compared them with SOD1G93A 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 SOD1G93A pathology, slowing disease progression and significantly extending survival by ~ 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. Keywords HMGB1 . DAMP . Neuroinflammation . Innate immune system
Introduction Amyotrophic lateral sclerosis (ALS) is a progressive heterogeneous neurodegenerative disease. It is characterized by the
* Trent M. Woodruff [email protected] John D. Lee [email protected] Tanya S. McDonald [email protected] Jenny N. T. Fung [email protected] 1
School of Biomedical Sciences, The University of Queensland, St Lucia, Brisbane, QLD 4072, Australia
2
Queensland Brain Institute, the University of Queensland, St Lucia, Brisbane, QLD 4072, Australia
degeneration of the upper motor neurons in the motor cortex and lower motor neurons in the brainstem and spinal cord leading to muscle denervation, and atrophy, resulting in paralysis and eventual death due to respiratory muscle failure. The mechanisms leading to motor neuron death in ALS are still unclear, but an emerging body of evidence suggests that immune and inflammatory factors could contribute to the progression of the disease [1–3]. The receptor for the advanced glycation end product (RAGE) is a member of the immunoglobulin
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