Genetic Deletion of Adenosine A 2A Receptors Attenuates Aged‐Related Alterations of Glial Cells Morphology and of Inflammasome in the Hippocampus and Prefrontal Cortex of Mice

Although brain disorders are the major burden of disease in Western countries and their incidence increases sharply with aging, the biological basis of brain aging is still poorly explored. Glial cells, namely microglia and astrocytes, maintain brain homeostasis and mount neuroinflammation that can contribute to age‐related deterioration of brain functions. The purinergic system, particularly adenosine A 2A (A 2A R) and P2X 7 (P2X 7 R) receptors, modulates glial function and neuroinflammation. The present study aims to investigate how aging affects microglia and astrocytes morphology and the NRLP3 inflammasome complex, a key driver of the inflammatory process, and if the genetic deletion of A 2A R has a protective role in inflammaging. We resorted to wild‐type and A 2A R knockout mice with 3‐ and 24‐ month‐old to investigate alterations in microglia and astrocytes morphology, in P2X 7 R, and in related NRLP3 inflammasome components in the hippocampus and prefrontal cortex. Data show that brain aging alters the tridimensional structure of microglia and astrocytes in the hippocampus and prefrontal cortex. Aging decreased the levels of P2X 7 R and of inflammasome components, NLRP3 and caspase 1, in the hippocampus. Remarkably, A 2A R knockout abrogated age‐related morphological changes of glial cells in both brain structures. Also, the decreased hippocampal P2X 7 R levels and the alterations in NLRP3 levels in both hippocampus and cortex, were no longer present in aged A 2A R knockout mice. These findings indicate that A 2A R might bolster NRLP3 inflammasome activation associated with an age‐related neuroinflammation, and A 2A R blockade might promote healthy brain aging.