Receptor for AGE (RAGE) Signal Transduction in Amyotrophic Lateral Sclerosis: In Vivo Imaging and Novel Therapeutic Approaches
Abstract
We hypothesized that the receptor for advanced glycation end products (RAGE) is implicated in the pathogenesis of ALS, at least in part through microglial perturbation. Our findings: (1) RAGE-positive Cd11b-positive cells are increased in the ventral horn of male and femaleSOD1G93A mouse lumbar spinal cord and male wild-type mice displayed higher proportions of RAGE-positive Cd11b cells than female wild-type mice. (2) In combined male and female SOD1G93A mice, microglia deletion of Ager in the ALS mouse background prolongs survival and slows loss of body weight and motor function. We identified an independent negative effect of the Cre recombinase mousseline in the ALS background (Cx3cr1ERT2 cre). At this time, we are finalizing all mouse groups (male and female) so that ample power is achieved for each line in order to finalize conclusions. (3) PET imaging using tracers to mark inflammation suggests higher spinal cord inflammation at day 100 and day 130 of life in SOD1G93A mice vs. controls. (4) Orally available (medicated chow) small molecule antagonists of RAGE/DIAPH1 are being tested in SOD1G93A mice. Collectively, our data suggest deleterious roles for RAGE in ALS and indicate that further testing of this concept is warranted in this disease.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2019
- Accession Number
- AD1082024
Entities
People
- Ann M. Schmidt
Organizations
- Grossman School of Medicine