Receptor for AGE (RAGE) Signal Transduction in Amyotrophic Lateral Sclerosis: In Vivo Imaging and Novel Therapeutic Approaches
[Technical Report, Final Report]
NEW YORK UNIV NY
Pagination or Media Count:
ALS is a fatal neurodegenerative disorder resulting in paralysis of skeletal muscle and respiratory failure, with higher incidence in persons with military service. Pathological levels of receptor for advanced glycation end products RAGE ligands and RAGE accumulate in ALS in the CNS in humans and mice. We previously treated male SOD1G93A mice with sRAGE, the extracellular ligand-binding domains of RAGE sRAGE prolonged life span and improved motor function vs. vehicle. sRAGE is not a viable therapeutic agent. During this grant, we showed1 RAGE expression in microglia in the ALS spinal cord exerts maladaptive effects on survival and motor function in male SOD1G93A mice. 2 We showed that a key chemical probe,RAGE229 small molecule antagonist of RAGE, shows promise to affect survival and motor function in SOD1G93A mice and to reduce pathological neuroinflammation in the spinal cord. 3 We tracked mitochondrial metabolism in SOD1G93A mice compared to non-SOD1G93A mice or SOD1G93A mice treated with RAGE229, vehicle-treated SOD1G93A mice showed the lowestmitochondrial tracer uptake in the spinal cord. CD11B microglia content in the ventral horn was reduced in the RAGE229 vs. vehicle mice. This work indicates that is logical to target RAGE-DIAPH1 in ALS.
- Medicine and Medical Research