Abstract
Hydrocephalus is a common and serious neuropathological condition characterized by disrupted cerebrospinal fluid (CSF) circulation, which lacks effective pharmacotherapy. Here, we demonstrate that adenosine A2A receptor (A2AR) signaling in the choroid plexus (ChP) is a trigger of hydrocephalus. Adenosine levels are increased in the CSF of hydrocephalus patients and mice, together with elevated ChP-A2AR density. Accordingly, continued infusion of adenosine for 14 days or transgenic ChP-A2AR overexpression is sufficient to drive CSF hypersecretion and ventriculomegaly. Conversely, selective knockdown of ChP-A2AR reduces CSF production and ameliorates CSF hypersecretion and ventriculomegaly induced by autologous blood and kaolin. Furthermore, we unveil ChP-A2AR signali…
Abstract
Hydrocephalus is a common and serious neuropathological condition characterized by disrupted cerebrospinal fluid (CSF) circulation, which lacks effective pharmacotherapy. Here, we demonstrate that adenosine A2A receptor (A2AR) signaling in the choroid plexus (ChP) is a trigger of hydrocephalus. Adenosine levels are increased in the CSF of hydrocephalus patients and mice, together with elevated ChP-A2AR density. Accordingly, continued infusion of adenosine for 14 days or transgenic ChP-A2AR overexpression is sufficient to drive CSF hypersecretion and ventriculomegaly. Conversely, selective knockdown of ChP-A2AR reduces CSF production and ameliorates CSF hypersecretion and ventriculomegaly induced by autologous blood and kaolin. Furthermore, we unveil ChP-A2AR signaling as a molecular mechanism linking brain insults with CSF hypersecretion through parallel PI3K/Akt-dependent activation of SPAK phosphorylation and NF-κB-dependent transcriptional regulation of ATP1A2. Lastly, the A2AR antagonist KW6002 protects against hydrocephalus induced by autologous blood and kaolin, offering a novel treatment for hydrocephalus by repurposing the FDA-approved A2AR antagonist istradefylline.
Data availability
RNA-seq datasets were deposited into BioProject database under number PRJNA1353615. All sequencing data is publicly available. Source data are provided with this paper.
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Acknowledgements
This research received financial support from the following sources: the Research Fund for International Senior Scientists (Grant No. 82150710558 to J.F.C.), the National Natural Science Foundation of China (Grant No. 31800903 to W.Z.), the Zhejiang Provincial Natural Science Foundation of China (Grant No. LMS25H090008 to W.Z.), the Science & Technology Initiative STI2030-Major Projects (Grant No. 2021ZD0203400 to J.F.C.), the Department of Science and Technology of Zhejiang Province (Grant No. 2023ZY1011 to W.Z.), the Ningbo Major Research and Development Plan Program (Grant No. 2023Z196 to W.Z.), the Ningbo Medical Science and Technology Project (Grant No.2023Y03 to Z.Y.L.) and the Ningbo Medical and Health Leading Academic Discipline Project (Grant No. 2022‑F04 to H.C.W.).
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Author notes
These authors contributed equally: Wu Zheng, Lanxin Hu, Yuwen Yang.
Authors and Affiliations
The Eye-Brain Research Center and Molecular Neuropharmacological Lab, State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
Wu Zheng, Lanxin Hu, Yuwen Yang, Xuhang Li, Wangchao Chen, Yiwei Jiang, Yuhan Chen, Cheng Zheng & Jiang-Fan Chen 1.
Department of Neurology, the Affiliated Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
Wu Zheng & Zhongyue Lv 1.
Oujiang Laboratory (Zhejiang Laboratory for Regenerative Medicine, Vision and Brain Health), School of Ophthalmology & Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
Lanxin Hu, Yuwen Yang & Jiang-Fan Chen 1.
Key Laboratory for Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang, China
Jia Wu 1.
Department of Neurosurgery, Ningbo Medical Center Lihuili Hospital, Ningbo University, Ningbo, Zhejiang, China
Hongcai Wang, Shiwei Li & Kuan Feng 1.
The Department of Neurology, Daping Hospital, The Arm Medical University, Chongqing, China
Yanjiang Wang 1.
CNC-Center for Neuroscience and Cell Biology, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
Rodrigo A. Cunha
Authors
- Wu Zheng
- Lanxin Hu
- Yuwen Yang
- Xuhang Li
- Jia Wu
- Wangchao Chen
- Yiwei Jiang
- Yuhan Chen
- Hongcai Wang
- Shiwei Li
- Kuan Feng
- Cheng Zheng
- Yanjiang Wang
- Rodrigo A. Cunha
- Zhongyue Lv
- Jiang-Fan Chen
Contributions
W.Z. and J.F.C. designed and conceived the research; W.Z., L.X.H., Y.W.Y., X.H.L., W.C.C. and Y.W.J. prepared the tables and figures; W.Z., L.X.H., Y.W.Y., X.H.L., J.W., W.C.C., Y.W.J., Y.H.C. and C.Z. performed the experiments and analysis; Z.Y.L., H.C.W., Y.J.W., S.W.L. and K.F. collected the CSF from hydrocephalus patients and controls. W.Z., R.A.C. and J.F.C. wrote and revised the manuscript.
Corresponding authors
Correspondence to Wu Zheng, Zhongyue Lv or Jiang-Fan Chen.
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Zheng, W., Hu, L., Yang, Y. et al. Aberrant adenosine A2A receptor signaling in the choroid plexus drives CSF hypersecretion and ventriculomegaly in hydrocephalus. Nat Commun (2025). https://doi.org/10.1038/s41467-025-66776-8
Received: 24 February 2025
Accepted: 14 November 2025
Published: 07 December 2025
DOI: https://doi.org/10.1038/s41467-025-66776-8