Potentiation of cannabinoid signaling in microglia by adenosine A_2A receptor antagonists

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 (A2AR) 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. 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 are able to 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. This heteromer‐specific feature suggests that A2AR antagonists would potentiate, via microglia, the neuroprotective action of endocannabinoids with implications for AD therapy.

Endocannabinoid Signaling Collapse Mediates Stress-Induced Amygdalo-Cortical Strengthening

“…Interestingly, the induction of eCB-LTD is highly variable based on the stimulation paramaters and the brain region being examined, suggesting that there are multiple mechanistically distinct modes of eCB-LTD. More recent studies have even demonstrated astrocytic and microlical eCB signaling as a crucial regulators of synaptic plasticity, adding further complexity to the physiological role of eCBs (Franco et al, 2019;Navarrete and Araque, 2010;Navarrete et al, 2014).…”

Adenosine A2AReceptors in Substance Use Disorders: A Focus on Cocaine

“…In mice, opposing functional interactions between A 2A Rs and CB 1 receptors in the hippocampus, as well as the Δ 9 -THC-induced cognitive impairment being blocked by an A 2A R antagonist, were demonstrated [ 131 ]. Such interactions might also occur in the microglia [ 132 ]; however, this must be confirmed in further studies.…”

Changes in the Hippocampal Genes Transcriptome in Depression Model Mice upon Intranasal Exposure to M2 Macrophage Secretome Factors

“…Этот факт означает, что ABHD12 является важнейшим фактором, регулирующим внеклеточный уровень 2-АГ и передачу сигналов CB рецепторам. Активность именно этой гидролазы может определять судьбу нейронного трансмиттерного сигнала [53,54] и «воспаленное» состояние микроглии [60] (рис. 1).…”

“…Результаты, полученные в работах в последнее время, свидетельствуют о важном потенциале микроглиальных аденозиновых рецепторов в нейропротекции, поскольку они ослабляют воспаление и способствуют поляризации M2 [2,60]. Более того, установлено, что аденозиновый рецептор A2A находится в физическом контакте с каннабиноидным рецептором СВ2.…”