Connexin43 hemichannel blockade turns microglia neuroprotective and mitigates cognitive deficits in a mouse model of amyloidosis.

1. Nat Commun. 2025 Jul 1;16(1):5621. doi: 10.1038/s41467-025-60746-w.

Connexin43 hemichannel blockade turns microglia neuroprotective and mitigates cognitive deficits in a mouse model of amyloidosis.

Su Y(1)(2), Li H(1)(2), Zhang W(3), Tao S(3), Wang Q(1)(2), Zhang X(3), Zhou M(4), Huang X(1), Wang C(1)(2), Tang Y(5), Chen H(6), Verkhratsky A(7)(8)(9)(10)(11), Zha Z(12), Niu J(13)(14), Yi C(15)(16)(17)(18).

Author information: (1)Research Centre, Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China. (2)Department of Histology and Embryology, Third Military Medical University, Chongqing, China. (3)School of Food and Biological Engineering, Hefei University of Technology, Hefei, China. (4)Department of Central Laboratory, Qianjiang Hospital, Chongqing University, Qianjiang, Chongqing, China. (5)International Joint Research Centre on Purinergic Signalling/School of Health and Rehabilitation, Chengdu University of Traditional Chinese Medicine, Chengdu, China. (6)School of Life Sciences, Faculty of Science, University of Technology Sydney, Ultimo, Australia. (7)Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK. (8)Department of Neurosciences, University of the Basque Country, Leioa, Bizkaia, Spain. (9)IKERBASQUE Basque Foundation for Science, Bilbao, Spain. (10)Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, China. (11)Department of Forensic Analytical Toxicology, School of Forensic Medicine, China Medical University, Shenyang, China. (12)School of Food and Biological Engineering, Hefei University of Technology, Hefei, China. zbzha@hfut.edu.cn. (13)Department of Histology and Embryology, Third Military Medical University, Chongqing, China. jianqinniu@tmmu.edu.cn. (14)Chongqing Key Laboratory of Neurobiology, Chongqing, China. jianqinniu@tmmu.edu.cn. (15)Research Centre, Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, China. yichj@mail.sysu.edu.cn. (16)Guangdong Provincial Key Laboratory of Digestive Cancer Research, Shenzhen, China. yichj@mail.sysu.edu.cn. (17)Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou, China. yichj@mail.sysu.edu.cn. (18)Shenzhen Key Laboratory of Chinese Medicine Active Substance Screening and Translational Research, Shenzhen, China. yichj@mail.sysu.edu.cn.

Alzheimer’s disease (AD), the leading cause of senile dementia, lacks effective therapies. While microglia are central to AD pathology, key therapeutic targets remain unclear. Here we identify microglial connexin43 (Cx43) hemichannels as a regulator of microglial reactivity in AD, positioning them as a promising therapeutic target. Post-mortem AD patient tissue showed elevated Cx43 levels in periplaque microglia. In the APPswe/PS1dE9 (APP/PS1) mouse model of amyloidosis, we demonstrated that microglial Cx43 hemichannels correlated with microglial malfunction, which in turn exacerbated β-amyloid pathology. Ablation of microglial Cx43 hemichannels by genetic knockout shifts microglia to a neuroprotective phenotype, enhancing the microglia-plaque interaction while suppressing neurotoxicity, thereby mitigating the progression of AD-like pathology. We developed TAT-Cx43@LNPs, a Cx43 hemichannel-targeting peptide delivered by a lipid nanoparticle system, which effectively delayed and rescued β-amyloid-related neuropathology and cognitive impairment in APP/PS1 mice. This study provides evidence for advancing Cx43 hemichannel targeting therapy into clinical trials.

© 2025. The Author(s).

DOI: 10.1038/s41467-025-60746-w PMCID: PMC12219535 PMID: 40595567 [Indexed for MEDLINE]

Conflict of interest statement: Competing interests: The authors declare no competing interests.