IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-60746-w.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-60746-w
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-60746-w?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Elizabeth Spangenberg & Paul L. Severson & Lindsay A. Hohsfield & Joshua Crapser & Jiazhong Zhang & Elizabeth A. Burton & Ying Zhang & Wayne Spevak & Jack Lin & Nicole Y. Phan & Gaston Habets & Andrey, 2019. "Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model," Nature Communications, Nature, vol. 10(1), pages 1-21, December.
    2. Guilin Pi & Di Gao & Dongqin Wu & Yali Wang & Huiyang Lei & Wenbo Zeng & Yang Gao & Huiling Yu & Rui Xiong & Tao Jiang & Shihong Li & Xin Wang & Jing Guo & Si Zhang & Taoyuan Yin & Ting He & Dan Ke & , 2020. "Posterior basolateral amygdala to ventral hippocampal CA1 drives approach behaviour to exert an anxiolytic effect," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Ren-Wen Han & Zi-Yi Zhang & Chen Jiao & Ze-Yu Hu & Bing-Xing Pan, 2024. "Synergism between two BLA-to-BNST pathways for appropriate expression of anxiety-like behaviors in male mice," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Nóra Baligács & Giulia Albertini & Sarah C. Borrie & Lutgarde Serneels & Clare Pridans & Sriram Balusu & Bart Strooper, 2024. "Homeostatic microglia initially seed and activated microglia later reshape amyloid plaques in Alzheimer’s Disease," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Laura K. Hamilton & Gaël Moquin-Beaudry & Chenicka L. Mangahas & Federico Pratesi & Myriam Aubin & Anne Aumont & Sandra E. Joppé & Alexandre Légiot & Annick Vachon & Mélanie Plourde & Catherine Mounie, 2022. "Stearoyl-CoA Desaturase inhibition reverses immune, synaptic and cognitive impairments in an Alzheimer’s disease mouse model," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    4. Qingtao Sun & Jianping Zhang & Anan Li & Mei Yao & Guangcai Liu & Siqi Chen & Yue Luo & Zhi Wang & Hui Gong & Xiangning Li & Qingming Luo, 2022. "Acetylcholine deficiency disrupts extratelencephalic projection neurons in the prefrontal cortex in a mouse model of Alzheimer’s disease," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    5. Alicia Bedolla & Elliot Wegman & Max Weed & Messiyah K. Stevens & Kierra Ware & Aditi Paranjpe & Anastasia Alkhimovitch & Igal Ifergan & Aleksandr Taranov & Joshua D. Peter & Rosa Maria Salazar Gonzal, 2024. "Adult microglial TGFβ1 is required for microglia homeostasis via an autocrine mechanism to maintain cognitive function in mice," Nature Communications, Nature, vol. 15(1), pages 1-25, December.
    6. Candela Sánchez-Bellot & Rawan AlSubaie & Karyna Mishchanchuk & Ryan W. S. Wee & Andrew F. MacAskill, 2022. "Two opposing hippocampus to prefrontal cortex pathways for the control of approach and avoidance behaviour," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    7. Huiling Yu & Liping Chen & Huiyang Lei & Guilin Pi & Rui Xiong & Tao Jiang & Dongqin Wu & Fei Sun & Yang Gao & Yuanhao Li & Wenju Peng & Bingyu Huang & Guoda Song & Xin Wang & Jingru Lv & Zetao Jin & , 2022. "Infralimbic medial prefrontal cortex signalling to calbindin 1 positive neurons in posterior basolateral amygdala suppresses anxiety- and depression-like behaviours," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    8. Yannick Fotio & Alex Mabou Tagne & Erica Squire & Hye-lim Lee & Connor M. Phillips & Kayla Chang & Faizy Ahmed & Andrew S. Greenberg & S. Armando Villalta & Vanessa M. Scarfone & Gilberto Spadoni & Ma, 2024. "NAAA-regulated lipid signaling in monocytes controls the induction of hyperalgesic priming in mice," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    9. Noah R. Johnson & Peng Yuan & Erika Castillo & T. Peter Lopez & Weizhou Yue & Annalise Bond & Brianna M. Rivera & Miranda C. Sullivan & Masakazu Hirouchi & Kurt Giles & Atsushi Aoyagi & Carlo Condello, 2023. "CSF1R inhibitors induce a sex-specific resilient microglial phenotype and functional rescue in a tauopathy mouse model," Nature Communications, Nature, vol. 14(1), pages 1-23, December.
    10. Suvra Nath & Jose C. Martínez Santamaría & Yu-Hsuan Chu & James S. Choi & Pasquale Conforti & Jia-Di Lin & Roman Sankowski & Lukas Amann & Christos Galanis & Kexin Wu & Sachin S. Deshpande & Andreas V, 2024. "Interaction between subventricular zone microglia and neural stem cells impacts the neurogenic response in a mouse model of cortical ischemic stroke," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    11. Rasmus Berglund & Yufei Cheng & Eliane Piket & Milena Z. Adzemovic & Manuel Zeitelhofer & Tomas Olsson & Andre Ortlieb Guerreiro-Cacais & Maja Jagodic, 2024. "The aging mouse CNS is protected by an autophagy-dependent microglia population promoted by IL-34," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60746-w. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.