Astrocytic Connexin43 in Alzheimer's disease: mechanisms, interaction with P2 receptors, and therapeutic potential

Pathogenesis of Alzheimer's disease (AD) is closely linked to functional abnormalities of the gap junction protein Connexin43 (Cx43) in astrocytes. Cx43 mediates ion homeostasis, metabolic support, and glial network signalling through formation of gap junctions and hemichannels. However, in AD, aberrant activation of Cx43 hemichannels exacerbates disrupted calcium signalling, promotes the release of ATP and glutamate, and amplifies neuroinflammation, ultimately contributing to a self-perpetuating pathological loop. This review provides a comprehensive summary of the pathophysiological roles of Cx43 in AD, with emphasis on its hemichannel function, and the interaction between Cx43 hemichannel and P2 receptors in AD pathogenesis. We further illustrate the potential contribution of non-channel function of Cx43 to reactive astrogliosis, and discuss recent preclinical advances in therapeutic strategies targeting Cx43, such as connexin-mimetic peptides and small-molecule inhibitors.