Novel insights into RAGE signaling pathways during the progression of amyotrophic lateral sclerosis in RAGE-deficient SOD1 G93A mice.

Amyotrophic lateral sclerosis (ALS) is neurodegenerative disease characterized by a progressive loss of motor neurons resulting in paralysis and muscle atrophy. One of the most prospective hypothesis on the ALS pathogenesis suggests that excessive inflammation and advanced glycation end-products (AGEs) accumulation play a crucial role in the development of ALS in patients and SOD1 G93A mice. Hence, we may speculate that RAGE, receptor for advanced glycation end-products and its proinflammatory ligands such as: HMGB1, S100B and CML contribute to ALS pathogenesis. The aim of our studies was to decipher the role of RAGE as well as provide insight into RAGE signaling pathways during the progression of ALS in SOD1 G93A and RAGE-deficient SOD1 G93A mice. In our study, we observed alternations in molecular pattern of proinflammatory RAGE ligands during progression of disease in RAGE KO SOD1 G93A mice compared to SOD1 G93A mice. Moreover, we observed that the amount of beta actin (ACTB) as well as Glial fibrillary acidic protein (GFAP) was elevated in SOD1 G93A mice when compared to mice with deletion of RAGE. These data contributes to our understanding of implications of RAGE and its ligands in pathogenesis of ALS and highlight potential targeted therapeutic interventions at the early stage of this devastating disease. Moreover, inhibition of the molecular cross-talk between RAGE and its proinflammatory ligands may abolish neuroinflammation, gliosis and motor neuron damage in SOD1 G93A mice. Hence, we hypothesize that attenuated interaction of RAGE with its proinflammatory ligands may improve well-being and health status during ALS in SOD1 G93A mice. Therefore, we emphasize that the inhibition of RAGE signaling pathway may be a therapeutic target for neurodegenerative diseases.

Nowicka N ，Zglejc-Waszak K ，Juranek J ，Korytko A ，Wąsowicz K ，Chmielewska-Krzesińska M ，Wojtkiewicz J ... -  《PLoS One》

The Involvement of RAGE and Its Ligands during Progression of ALS in SOD1 G93A Transgenic Mice.

Nowicka N ，Szymańska K ，Juranek J ，Zglejc-Waszak K ，Korytko A ，Załęcki M ，Chmielewska-Krzesińska M ，Wąsowicz K ，Wojtkiewicz J ... -  《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》

Microglia RAGE exacerbates the progression of neurodegeneration within the SOD1(G93A) murine model of amyotrophic lateral sclerosis in a sex-dependent manner.

MacLean M ，Juranek J ，Cuddapah S ，López-Díez R ，Ruiz HH ，Hu J ，Frye L ，Li H ，Gugger PF ，Schmidt AM ... -  《Journal of Neuroinflammation》

Absence of Receptor for Advanced Glycation End Product (RAGE) Reduces Inflammation and Extends Survival in the hSOD1(G93A) Mouse Model of Amyotrophic Lateral Sclerosis.

Lee JD ，McDonald TS ，Fung JNT ，Woodruff TM ... -  《-》

Effects of RAGE inhibition on the progression of the disease in hSOD1(G93A) 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 hSOD1G93A 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 hSOD1G93A mice. To evaluate the relevance of this neurotoxic mechanism in ALS pathology, we assessed the therapeutic potential of FPS-ZM1 in hSOD1G93A mice. FPS-ZM1 treatment significantly improved hind-limb grip strength in hSOD1G93A 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 hSOD1G93A mice. Maintenance of hind-limb grip strength was also observed in hSOD1G93A mice with RAGE haploinsufficiency [hSOD1G93A ;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 hSOD1G93A 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.

Liu L ，Killoy KM ，Vargas MR ，Yamamoto Y ，Pehar M ... -  《Pharmacology Research & Perspectives》