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Glia. 2019 Dec;67(12):2410-2423. doi: 10.1002/glia.23694. Epub 2019 Aug 19.

Potentiation of cannabinoid signaling in microglia by adenosine A2A receptor antagonists.

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Molecular Neurobiology Laboratory, Department of Biochemistry and Molecular Biomedicine, Universitat de Barcelona, Barcelona, Spain.
Centro de Investigación en Red, Enfermedades Neurodegenerativas (CiberNed), Instituto de Salud Carlos III, Madrid, Spain.
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
Phytoplant Research S.L., Córdoba, Spain.
Department de Bioquímica i Biologia Molecular, Institut de Neurociències, Universitat Autònoma de Barcelona, Barcelona, Spain.
Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Sciences, Universitat de Barcelona, Barcelona, Spain.


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 A2A (A2A 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. A2A 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 A2A -CB2 receptor heteromer (A2A -CB2 Het). Particularly relevant is the upregulation of A2A -CB2 Het 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 CB2 R-mediated signaling. This heteromer-specific feature suggests that A2A R antagonists would potentiate, via microglia, the neuroprotective action of endocannabinoids with implications for AD therapy.


Alzheimer's disease; CB2 receptors; GPCR; MAPK pathway; THC; heteromer; microglia


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