Rage deletion increases anti-oxidant and anti-inflammatory biochemical profiles in human app transgenic mice

Abstract

The Receptor for Advanced Glycation Endproducts (RAGE) is a pattern recognition receptor that binds structurally diverse ligands associated with Alzheimer's disease (AD) including amyloid beta (Aβ) peptides. RAGE expression is upregulated in Alzheimer's brains while the anti-oxidant reduced glutathione (GSH) is deficient in brains from early and middle staged AD patients. Preclinical studies demonstrate RAGE regulates many pathologies observed in AD related to oxidative stress: chronic inflammation, Aβ transport, neurotoxicity, and metabolic dysfunction. Genetic deletion or antagonism of RAGE in vivo improves AD pathogenesis in transgenic mouse models. Since RAGE is associated with metabolic dysfunction, we determined the effect of genetic RAGE deletion on biochemical profiles in APP mice. CSF, plasma and brain samples were collected from mice 9 and 12 months old that over express human APP (amyloid precursor protein, Swedish and London mutations; APPSwe-Lon; APPtg x RAGE+/+ and APPtg x RAGE-/-). Biochemicals were analyzed using metabolomics platform technology (Metabolon, Inc.). Metabolites were also compared from cellular lysates of cultured mouse aortic smooth muscle cells obtained from either wild-type or RAGE-null mice. A number of biochemicals were significantly different between RAGE null and APP overexpressing control mice representing anti-oxidant, inflammatory, cholesterol and phospholipid metabolic pathways. RAGE null mice have increased levels of antioxidants (glutathione) and decreased levels of inflammatory precursor biochemical's (arachidonic, eicospentanoic acid) in brain. Plasma γ-glutamyl dipeptides were increased at 9 and 12 months, suggesting a higher level of glutathione biosynthesis. Analysis of vascular smooth muscle cells in vitro from RAGE null mice recapitulated the anti-oxidant metabolite profile. These cells have decreased intermediates of glycolysis and increased intermediates in the TCA cycle, increased glutathione and NAD levels, and increased levels of γ-glutamyl dipeptides. The metabolome profile suggests RAGE deletion increases the anti-oxidant capacity of brain in APP mice. This data suggests RAGE deletion alters the CNS response to oxidative stress and inflammation, providing neuroprotection during disease progression.