Potentiation of cannabinoid signaling in microglia by adenosine A 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 (A R) and cannabinoid CB (CB R) GPCRs in microglia is that their expression is upregulated in Alzheimer's disease (AD). On the one hand, CB R seems a target for neuroprotection, delaying neurodegenerative processes like those associated to AD or Parkinson's diseases. A 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 -CB receptor heteromer (A -CB Het). Particularly relevant is the upregulation of A -CB Het expression in samples from the APP , AD transgenic mice model. The most relevant finding, confirmed in both heterologous cells and in primary cultures of microglia, was that blockade of A receptors results in increased CB R-mediated signaling. This heteromer-specific feature suggests that A R antagonists would potentiate, via microglia, the neuroprotective action of endocannabinoids with implications for AD therapy.