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

1. Neuropharmacology. 2026 Jan 1;282:110705. doi: 10.1016/j.neuropharm.2025.110705. Epub 2025 Oct 7. Astrocytic Connexin43 in Alzheimer's disease: mechanisms, interaction with P2 receptors, and therapeutic potential. Xiong W(1), Su Y(2), Verkhratsky A(3), Yi C(4). Author information: (1)Department of Geriatrics, Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China. (2)Department of Geriatrics, Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China. Electronic address: suyixun@u.nus.edu. (3)Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK; Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang, China; International Joint Research Centre on Purinergic Signalling of Sichuan Province Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China; Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China; Shenzhen Key Laboratory of Chinese Medicine Active Substance Screening and Translational Research, Shenzhen, 518107, China. Electronic address: Alexej.Verkhratsky@manchester.ac.uk. (4)Department of Geriatrics, Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China; Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, China; Shenzhen Key Laboratory of Chinese Medicine Active Substance Screening and Translational Research, Shenzhen, 518107, China. Electronic address: yichj@mail.sysu.edu.cn. 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. Copyright © 2025 Elsevier Ltd. All rights reserved. DOI: 10.1016/j.neuropharm.2025.110705 PMID: 41062060 [Indexed for MEDLINE] Conflict of interest statement: Declaration of competing interest The authors declare no conflicts of interest.