Potentiation of cannabinoid signaling in microglia by adenosine A2A receptor antagonists. Issue 12 (19th August 2019)

• Record Type: Journal Article
• Authors: Franco, Rafael; Reyes‐Resina, Irene; Aguinaga, David; Lillo, Alejandro; Jiménez, Jasmina; Raïch, Iu; Borroto‐Escuela, Dasiel O.; Ferreiro‐Vera, Carlos; Canela, Enric I.; Sánchez de Medina, Verónica; del Ser‐Badia, Anna; Fuxe, Kjell; Saura, Carlos A.; Navarro, Gemma
• Is Part Of: Glia. Volume 67:Issue 12(2019)
• Page Start: 2410
• Page End: 2423
• Publication Date: 2019-08-19
• Subjects: Alzheimer's disease -- CB2 receptors -- GPCR -- heteromer -- MAPK pathway -- microglia -- THC; Neuroglia -- Periodicals; Neurology -- Periodicals; 611.0188
• DOI: 10.1002/glia.23694
• Languages: English
• ISSNs: 0894-1491

Abstract

Abstract: 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. Main Points: Adenosine A2A/cannabinoid CB2 receptor heteromers, expressed in microglia from Alzheimer's disease (AD) models, allow enhanced cannabinoid signaling upon A2A blockade. A2AR antagonists are promising to combat AD and other neurodegenerative diseases.