A2AR‐induced transcriptional deregulation in astrocytes: An in vitro study

Adenosine A2A receptors (A2AR) are modulators of various physiological processes essential for brain homeostasis and fine synaptic tuning. In certain neurodegenerative conditions, notably Alzheimer's disease (AD), A2ARs are pathologically upregulated in neurons but also in astrocytes. In that context, the use of A2ARs inhibitors, normalizing impaired receptor function, is seen as a potential therapeutic strategy. However, the impact of A2AR alterations, particularly in astrocytes, is not fully understood. Here, we investigated the effect of A2AR overexpression on transcriptional deregulation in primary astrocytic cultures. By performing whole transcriptome analysis, we found that A2AR overexpression promotes robust transcriptional changes, mostly affecting immune response, angiogenesis, and cell activation‐related genes. Importantly, we observed that treatment with SCH58261, a selective A2AR antagonist, restored the expression levels of several inflammatory and astrocytic activation‐related genes, such as Interleukin‐1beta and vimentin. This supports the notion that A2AR blockade could restore some astrocytic dysfunctions associated with abnormal A2AR expression, further arguing for a potential beneficial impact of receptor antagonists in A2AR‐induced transcriptional deregulation, inflammation, and astrogliosis. Overall, our findings provide novel insights into the putative impact of A2AR overexpression on transcriptional deregulation in astrocytes, thereby opening novel avenues for the use of A2AR antagonists as potential therapeutic strategy in neurodegenerative diseases.

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