Absence of receptor for advanced glycation end product (RAGE) reduces inflammation and extends survival in the hSOD1^G93A mouse model of amyotrophic lateral sclerosis

Abstract

1Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing motor neuron 2 degenerative disease that is without effective treatment. The receptor for advanced glycation 3 end products (RAGE) is a major component of the innate immune system that has been 4 implicated in ALS pathogenesis. However, the contribution of RAGE signaling to the 5 neuroinflammation that underlies ALS neurodegeneration remains unknown. The present study 6 therefore generated SOD1 G93A mice lacking RAGE, and compared them to SOD1 G93A 7 transgenic ALS mice in respect to disease progression (i.e. body weight, survival and muscle 8 strength), neuroinflammation and denervation markers in the spinal cord and tibialis anterior 9 muscle. We found that complete absence of RAGE signaling exerted a protective effect on 10 SOD1 G93A pathology, slowing disease progression and significantly extending survival by ~3 11 weeks, and improving motor function (rotarod and grip strength). This was associated with 12 reduced microgliosis, cytokines, innate immune factors (complement, TLRs, inflammasomes), 13 and oxidative stress in the spinal cord, and a reduction of denervation markers in the tibialis 14 anterior muscle. We also documented that RAGE mRNA expression was significantly 15 increased in the spinal cord and muscles of preclinical SOD1 and TDP43 models of ALS, 16 supporting a widespread involvement for RAGE in ALS pathology. In summary, our results 17 indicate that RAGE signalling drives neuroinflammation and contributes to neurodegeneration 18 in ALS, and highlights RAGE as a potential immune therapeutic target for ALS. 19 20 21 22 23 24

Amyotrophic lateral sclerosis alters the metabolic aging profile in patient derived fibroblasts

“…In turn, AGEs disrupt many cell functions including lipid synthesis and antioxidant defences, leading to inflammation and mitochondrial metabolism ( Aragno and Mastrocola, 2017 ). AGE receptors (RAGEs) have been found to be upregulated in spinal cord tissues isolated from ALS patients ( Juranek et al., 2015 ) and SOD1 mice lacking RAGE exhibited slower disease progression ( Lee et al., 2020 ). We have previously shown that fructose metabolism is reduced in fibroblasts and iAstrocytes from C9orf72 ALS cases and that the glyoxalase enzymes required for MGO removal are reduced in C9orf72 and SALS cases ( Allen et al., 2019a ; Allen et al., 2019b ).…”

Synaptic proteomics reveal distinct molecular signatures of cognitive change andC9ORF72repeat expansion in the human ALS cortex

“…In fact, numerous RAGE receptor ligands were upregulated in BA4 synapses, including several S100 calcium-binding proteins. RAGE receptor activation leads to the strong induction of pro-inflammatory signals and increased expression has been shown at presymptomatic stages of SOD1 and TDP43 mouse models of ALS [93]. Furthermore, RAGE knockout in hSOD1G93A mice leads to reduced inflammation and extended lifespan [93].…”

“…RAGE receptor activation leads to the strong induction of pro-inflammatory signals and increased expression has been shown at presymptomatic stages of SOD1 and TDP43 mouse models of ALS [93]. Furthermore, RAGE knockout in hSOD1G93A mice leads to reduced inflammation and extended lifespan [93]. In a recent human dataset a negative association between high RAGE expression and earlier age at death was observed [94], supporting our idea that ALSci patients have a more severe form of disease, and this may be driven by RAGE-dependent mechanisms.…”