Potentiation of cannabinoid signaling in microglia by adenosine A2A 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 (CB2R) GPCRs in microglia is that their expression is upregulated in Alzheimer's disease (AD). On the one hand, CB2R 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)-CB(2)Het). Particularly relevant is the upregulation of A(2A)-CB(2)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 CB2R-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.