Differential Gene Expression in Activated Microglia Treated with Adenosine A_2A Receptor Antagonists Highlights Olfactory Receptor 56 and T-Cell Activation GTPase-Activating Protein 1 as Potential Biomarkers of the Polarization of Activated Microglia

Abstract

Microglial activation often accompanies the plastic changes occurring in the brain of patients with neurodegenerative diseases. A2A and A3 adenosine receptors have been proposed as therapeutic targets to combat neurodegeneration. RNAseq was performed using samples isolated from lipopolysaccharide/interferon-γ activated microglia treated with SCH 58261, a selective A2A receptor antagonist, and with both SCH 58261 and 2-Cl-IB-MECA, a selective A3 receptor agonist. None of the treatments led to any clear microglial phenotype when gene expression for classical biomarkers of microglial polarization was assessed. However, many of the downregulated genes were directly or indirectly related to immune system-related events. Searching for genes whose expression was both significantly and synergistically affected when treated with the two adenosine receptor ligands, the AC122413.1 and Olfr56 were selected among those that were, respectively, upregulated and downregulated. We therefore propose that the products of these genes, olfactory receptor 56 and T-cell activation GTPase-activating protein 1, deserve attention as potential biomarkers of phenotypes that occur upon microglial activation.

Keywords

• adenosine A₃ receptor
• Alzheimer’s disease
• microglia
• neurodegeneration
• neuroinflammation
• Parkinson’s disease