Effects of RAGE inhibition on the progression of the disease in hSOD1 ALS mice.

Astrocytes play a key role in the progression of amyotrophic lateral sclerosis (ALS) by actively inducing the degeneration of motor neurons. Motor neurons isolated from receptor for advanced glycation end products (RAGE)-knockout mice are resistant to the neurotoxic signal derived from ALS-astrocytes. Here, we confirmed that in a co-culture model, the neuronal death induced by astrocytes over-expressing the ALS-linked mutant hSOD1 is prevented by the addition of the RAGE inhibitors FPS-ZM1 or RAP. These inhibitors also prevented the motor neuron death induced by spinal cord extracts from symptomatic hSOD1 mice. To evaluate the relevance of this neurotoxic mechanism in ALS pathology, we assessed the therapeutic potential of FPS-ZM1 in hSOD1 mice. FPS-ZM1 treatment significantly improved hind-limb grip strength in hSOD1 mice during the progression of the disease, reduced the expression of atrophy markers in the gastrocnemius muscle, improved the survival of large motor neurons, and reduced gliosis in the ventral horn of the spinal cord. However, we did not observe a statistically significant effect of the drug in symptoms onset nor in the survival of hSOD1 mice. Maintenance of hind-limb grip strength was also observed in hSOD1 mice with RAGE haploinsufficiency [hSOD1 ;RAGE(+/-)], further supporting the beneficial effect of RAGE inhibition on muscle function. However, no benefits were observed after complete RAGE ablation. Moreover, genetic RAGE ablation significantly shortened the median survival of hSOD1 mice. These results indicate that the advance of new therapies targeting RAGE in ALS demands a better understanding of its physiological role in a cell type/tissue-specific context.