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Targeting complement C3/C3aR pathway restores rejuvenation factor PF4 and mitigates neurocognitive impairments in age-related perioperative neurocognitive disorders

Molecular Psychiatry (2025)Cite this article

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Abstract

Perioperative neurocognitive disorders (PND), including postoperative delirium (POD), delayed neurocognitive recovery (dNCR) and postoperative neurocognitive disorder (PNCD), affect up to 10% of surgical patients older than 60 years, and currently there are no effective therapies to prevent PND. The gut microbiota is linked to PND through the gut-brain axis, promoting neuroinflammation via activation and proliferation of microglia and astrocytes in the central nervous system (CNS). In this study, we show that perioperative use of ceftriaxone, a long-acting β-lactam antibiotic, can prevent the development of PND in elderly surgical patients. This effect is associated with reduced serum complement C3 levels and increased levels of platelet factor 4 (PF4). Using an aged mouse model of PND, we found that C3/C3aR axis mediated the interaction of astroglia and microglia during the early stages of neuroinflammation. Genetic ablation or pharmacological blockade of C3/C3aR signaling pathway suppressed neuroinflammation and attenuated cognitive declines in PND. The C3/C3aR axis is essential for surgery-induced platelet count and circulating PF4 declines, and mice supplemented with recombinant PF4 exhibited reduced neuroinflammation and improved cognitive function. Together, our findings revealed the new roles of the C3/C3aR signaling pathway in platelet dysfunction and neuroinflammation in age-related PND, and these results highlight new potential therapeutic strategies for PND.

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Fig. 1: Perioperative use of ceftriaxone alleviates the upregulation of C3, platelet dysfunction and mild PNCD in elderly surgical patients.
Fig. 2: Interactions of astroglia and microglia at the early stage of PND.
Fig. 3: Blockage of C3 alleviates astroglia-microglia interaction and neuroinflammation.
Fig. 4: Blockage of C3 alleviates cognitive decline in mouse model of PND.
Fig. 5: Administration of recombinant PF4 attenuates neuroinflammation and cognitive decline in mouse model of PND.

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All materials and raw data are available from the corresponding authors upon reasonable request.

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Acknowledgements

We thank Dr. M. Gao for his technical assistance and for generous gift of CR2-crry. Z.L. received support from Youth Talents Project of the Fujian Young Eagle Program (grant No. FJHRSS2022173), Fujian Research and Training Grants for Young and Middle-aged Leaders in Healthcare (grant No. FJHCHR202326), National Natural Science Foundation of China (grant No.82171201), Joint Funds for the Innovation of Science and Technology of Fujian Province, China (grant No. 2021Y9073), Major Scientific Research Program for Young and Middle-aged Health Professionals of Fujian Province, China (grant No. 2023ZQNZD003), Z.Z. was supported by the Talent Program of Hubei University of Technology (grant No. GCC2024015). J.W. received support from the Startup Fund for Scientific Research, Fujian Medical University (Grant No. 2024QH1032).

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  1. These authors contributed equally: Jia-Li Wang, Cai-Hong Ye.

Authors and Affiliations

  1. Department of Anesthesiology, Fujian Medical University Union Hospital, 29 Xin-Quan Road, Fuzhou, Fujian, 350001, China

    Jia-Li Wang, Cai-Hong Ye, Zhong-Fa Teng, Shi-Lei Li, Mei-Hong Lin, Liang-Cheng Zhang, Shi-Shi Huang, Xiao-Ning Ren, Ning Zheng, Wen-Lin Wei & Zhong-Meng Lai

  2. Department of Urology, Fujian Medical University Union hospital, 29 Xin-Quan Road, Fuzhou, Fujian, 350001, China

    Kai Zhou

  3. Fujian Institute of Hematology, 29 Xin-Quan Road, Fuzhou, Fujian, 350001, China

    Li-Li Pan

  4. Fujian Provincial Key Laboratory on Hematology, 29 Xin-Quan Road, Fuzhou, Fujian, 350001, China

    Li-Li Pan

  5. Department of Hematology, Fujian Medical University Union Hospital, 29 Xin-Quan Road, Fuzhou, Fujian, 350001, China

    Li-Li Pan

  6. Department of Emergency Surgery, Fujian Medical University Union Hospital, 29 Xin-Quan Road, Fuzhou, Fujian, 350001, China

    Man-Duo Ouyan

  7. Department of Oral Surgery, Fujian Medical University Union Hospital, 29 Xin-Quan Road, Fuzhou, Fujian, 350001, China

    Zhi Zheng & Meng Lu

  8. Center for Advanced Vision Science, University of Virginia, Charlottesville, VA, USA

    Jing Zhang, Jingjing Zhang & Shao-Bin Wang

  9. Department of Ophthalmology, University of Virginia, Charlottesville, VA, USA

    Jing Zhang, Jingjing Zhang & Shao-Bin Wang

  10. Fujian Center for Safety Evaluation of New Drug, Fujian Medical University, Fuzhou, Fujian, China

    Pei-Chan Zheng

  11. Fujian Key Laboratory of Natural Medicine Pharmacology, School of Pharmacy, Fujian Medical University, Fuzhou, China

    Pei-Chan Zheng & Hui Zhang

  12. Center for Cellular Regulation and Molecular Pharmaceutics, School of Life and Health Sciences, Hubei University of Technology, Wuhan, 430068, China

    Zhenhuan Zhao

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Contributions

ZL, SW, and JW conceived and designed the study. JW, CY, SL, ML, XR, NZ, WW, ZT, MO, ZZ, ML, LZ, and SH performed the experiments. KZ, JW, JZ, JJZ, and CY conducted data analysis and visualization. PZ, HZ, ZL, and LP managed the project. ZL, SW, and JW drafted the original manuscript. ZZ contributed to the conceptualization and preparation of the revised manuscript. All authors reviewed and edited the final version of the manuscript.

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Correspondence to Zhenhuan Zhao, Shao-Bin Wang or Zhong-Meng Lai.

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Wang, JL., Ye, CH., Teng, ZF. et al. Targeting complement C3/C3aR pathway restores rejuvenation factor PF4 and mitigates neurocognitive impairments in age-related perioperative neurocognitive disorders. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-03103-z

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