A_2A R-induced transcriptional deregulation in astrocytes: An in vitro study

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.