CB2R seems a target for neuroprotection, delaying neurodegenerative processes like those associated to AD or Parkinson's diseases. A2AR 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 can physically interact and affect the signaling of each other, likely due to conformational changes within the A2A-CB2 receptor heteromer (A2A-CB2Het). Particularly relevant is the upregulation of A2A-CB2Het expression in samples from the APPSw,Ind AD transgenic mice model. The most relevant finding, confirmed in both heterologous cells and in primary cultures of microglia, was that blockade of A2A receptors results in increased CB2R-mediated signaling.