Potentiation of cannabinoid signaling in microglia by adenosine A_2A receptor antagonists

Neuroprotective M2-skewed microglia appear as promising to alter the course of neurodegenerative diseases and G protein-coupled receptors (GPCRs) are potential targets to achieve such microglial polarization. A common feature of adenosine A_2A (A_2A R) and cannabinoid CB₂ (CB₂ R) GPCRs in microglia is that their expression is upregulated in Alzheimer's disease (AD). On the one hand, CB₂ R seems a target for neuroprotection, delaying neurodegenerative processes like those associated to AD or Parkinson's diseases. A_2A R antagonists reduce amyloid burden and improve cognitive performance and memory in AD animal models. We here show a close interrelationship between these two receptors in microglia; they are able to physically interact and affect the signaling of each other, likely due to conformational changes within the A_2A -CB₂ receptor heteromer (A_2A -CB₂ Het). Particularly relevant is the upregulation of A_2A -CB₂ Het expression in samples from the APP_Sw ,_Ind AD transgenic mice model. The most relevant finding, confirmed in both heterologous cells and in primary cultures of microglia, was that blockade of A_2A receptors results in increased CB₂ R-mediated signaling. This heteromer-specific feature suggests that A_2A R antagonists would potentiate, via microglia, the neuroprotective action of endocannabinoids with implications for AD therapy.