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

Author

Listed:
  • Yixun Su

    (Seventh Affiliated Hospital of Sun Yat-sen University
    Third Military Medical University)

  • Hui Li

    (Seventh Affiliated Hospital of Sun Yat-sen University
    Third Military Medical University)

  • Wenjie Zhang

    (Hefei University of Technology)

  • Shi Tao

    (Hefei University of Technology)

  • Qi Wang

    (Seventh Affiliated Hospital of Sun Yat-sen University
    Third Military Medical University)

  • Xuan Zhang

    (Hefei University of Technology)

  • Mi Zhou

    (Chongqing University)

  • Xiaomin Huang

    (Seventh Affiliated Hospital of Sun Yat-sen University)

  • Chenmeng Wang

    (Seventh Affiliated Hospital of Sun Yat-sen University
    Third Military Medical University)

  • Yong Tang

    (Chengdu University of Traditional Chinese Medicine)

  • Hui Chen

    (University of Technology Sydney)

  • Alexei Verkhratsky

    (The University of Manchester
    University of the Basque Country
    IKERBASQUE Basque Foundation for Science
    Guangdong Provincial Key Laboratory of Digestive Cancer Research)

  • Zhengbao Zha

    (Hefei University of Technology)

  • Jianqin Niu

    (Third Military Medical University
    Chongqing Key Laboratory of Neurobiology)

  • Chenju Yi

    (Seventh Affiliated Hospital of Sun Yat-sen University
    Guangdong Provincial Key Laboratory of Digestive Cancer Research
    Guangdong Provincial Key Laboratory of Brain Function and Disease
    Shenzhen Key Laboratory of Chinese Medicine Active Substance Screening and Translational Research)

Abstract

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.

Suggested Citation

  • Yixun Su & Hui Li & Wenjie Zhang & Shi Tao & Qi Wang & Xuan Zhang & Mi Zhou & Xiaomin Huang & Chenmeng Wang & Yong Tang & Hui Chen & Alexei Verkhratsky & Zhengbao Zha & Jianqin Niu & Chenju Yi, 2025. "Connexin43 hemichannel blockade turns microglia neuroprotective and mitigates cognitive deficits in a mouse model of amyloidosis," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60746-w
    DOI: 10.1038/s41467-025-60746-w
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