A_2AR‐induced transcriptional deregulation in astrocytes: An in vitro study

Abstract

Abstract Adenosine A 2A receptors (A 2A R) are modulators of various physiological processes essential for brain homeostasis and fine synaptic tuning. In certain neurodegenerative conditions, notably Alzheimer's disease (AD), A 2A Rs are pathologically upregulated in neurons but also in astrocytes. In that context, the use of A 2A Rs inhibitors, normalizing impaired receptor function, is seen as a potential therapeutic strategy. However, the impact of A 2A R alterations, particularly in astrocytes, is not fully understood. Here, we investigated the effect of A 2A R overexpression on transcriptional deregulation in primary astrocytic cultures. By performing whole transcriptome analysis, we found that A 2A R overexpression promotes robust transcriptional changes, mostly affecting immune response, angiogenesis, and cell activation‐related genes. Importantly, we observed that treatment with SCH58261, a selective A 2A R antagonist, restored the expression levels of several inflammatory and astrocytic activation‐related genes, such as Interleukin‐1beta and vimentin. This supports the notion that A 2A R blockade could restore some astrocytic dysfunctions associated with abnormal A 2A R expression, further arguing for a potential beneficial impact of receptor antagonists in A 2A R‐induced transcriptional deregulation, inflammation, and astrogliosis. Overall, our findings provide novel insights into the putative impact of A 2A R overexpression on transcriptional deregulation in astrocytes, thereby opening novel avenues for the use of A 2A R antagonists as potential therapeutic strategy in neurodegenerative diseases.