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Peer-reviewedCC BYNeuron

P2RX7 drives inflammatory microglia and pathogenic extracellular vesicle secretion in tauopathy

  • Victor Bodart‐Santos1,2
  • Arun Reddy Ravula1,3
  • Yang You1,2
  • Mohammad Abdullah1,4
  • Zhi Ruan1,2
  • J. W Ellison1,2
  • Stephanie Radhakishun1,2
  • Nibedita Basu Ray1,2
  • Bridgette C. Melvin1,2
  • Aishe Kurti1,2
  • Zhewei Liang5,6
  • Yuta Sakai5,3
8 more authors
  • Daniel R. O’Brien5,7
  • Son N. Nguyen8,3
  • Scott A. Shaffer8,9
  • Lindsey Fiddes10,11
  • Oleg Butovsky12,13
  • Wolfdieter Springer1,14
  • Seiko Ikezu15,2
  • Seiko Ikezu16,2
16 affiliations
  1. 1Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
  2. 2Mayo Clinic Florida
  3. 3Mayo Clinic
  4. 4Mayo Clinic Floria
  5. 5Division of Computational Biology, Mayo Clinic, Rochester, MN 55905, USA
  6. 6Mayo Clinic Jacksonville
  7. 7Mayo Clinic Rochester
  8. 8Mass Spectrometry Facility, University of Massachusetts Chan Medical School, Shrewsbury, MA 01545, USA; Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA 01655, USA
  9. 9University of Massachusetts Chan Medical School
  10. 10Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
  11. 11UMASS Chan Medical School
  12. 12Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA
  13. 13University of Toronto
  14. 14Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School
  15. 15Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA. Electronic address: [email protected]
  16. 16Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Robert and Alene Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905, USA; Alzheimer's Disease Research Center, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: [email protected]
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Abstract

P2x purinoreceptor 7 (P2RX7), an ATP-gated ion channel, is known to play pivotal roles in the progression of Alzheimer's disease (AD), although its cell type-specific pathological mechanisms have yet to be elucidated. Here, we show that genetic deletion of P2rx7 mitigates brain atrophy, tau accumulation and cognitive impairment in PS19 tauopathy mice. Specific deletion of P2rx7 in microglia, but not astrocytes, significantly suppresses tau propagation from the entorhinal cortex to CA1 in the hippocampus, an early event in AD pathology. Single-cell (sc)-RNA sequencing of mouse brains revealed specific P2rx7 expression in microglia, inducing inflammatory changes accompanied by elevated extracellular vesicles (EVs) secretion in PS19 mice. Brain-derived EVs (BDEVs) proteome demonstrated that P2RX7 increases EV cargo loading of tau and mitochondrial molecules in BDEVs from PS19 mice, which was further validated by single-molecule super-resolution. Notably, following the injection of BDEVs isolated from PS19 mice with or without P2rx7 deficiency, the microglial transcriptome of recipient mice revealed enriched DNA-sensing and type II interferon signaling in response to BDEVs from PS19 mice, which was diminished in the group injected with P2rx7-deficient BDEVs. Thus, our results indicate that P2RX7 regulates EV-mediated tau and mitochondrial transfer and inflammatory activation in microglia with increased EV secretion, thereby contributing to tauopathy and neurodegeneration, highlighting the therapeutic potential of targeting the P2RX7-EV axis in AD.

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Cite

BibTeXRIS
BibTeX
@article{bodartsantos2026p2rx7,
  title = {{P2RX7 drives inflammatory microglia and pathogenic extracellular vesicle secretion in tauopathy}},
  author = {Victor Bodart‐Santos and Arun Reddy Ravula and Yang You and Mohammad Abdullah and Zhi Ruan and J. W Ellison and Stephanie Radhakishun and Nibedita Basu Ray and Bridgette C. Melvin and Aishe Kurti and Zhewei Liang and Yuta Sakai and Daniel R. O’Brien and Son N. Nguyen and Scott A. Shaffer and Lindsey Fiddes and Oleg Butovsky and Wolfdieter Springer and Seiko Ikezu and Seiko Ikezu},
  journal = {Neuron},
  year = {2026},
  month = nov,
  doi = {10.1016/j.neuron.2026.10.007},
  url = {https://doi.org/10.1016/j.neuron.2026.10.007},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - P2RX7 drives inflammatory microglia and pathogenic extracellular vesicle secretion in tauopathy
AU  - Victor Bodart‐Santos
AU  - Arun Reddy Ravula
AU  - Yang You
AU  - Mohammad Abdullah
AU  - Zhi Ruan
AU  - J. W Ellison
AU  - Stephanie Radhakishun
AU  - Nibedita Basu Ray
AU  - Bridgette C. Melvin
AU  - Aishe Kurti
AU  - Zhewei Liang
AU  - Yuta Sakai
AU  - Daniel R. O’Brien
AU  - Son N. Nguyen
AU  - Scott A. Shaffer
AU  - Lindsey Fiddes
AU  - Oleg Butovsky
AU  - Wolfdieter Springer
AU  - Seiko Ikezu
AU  - Seiko Ikezu
PY  - 2026
DA  - 2026/11/01
JO  - Neuron
DO  - 10.1016/j.neuron.2026.10.007
UR  - https://doi.org/10.1016/j.neuron.2026.10.007
AB  - P2x purinoreceptor 7 (P2RX7), an ATP-gated ion channel, is known to play pivotal roles in the progression of Alzheimer's disease (AD), although its cell type-specific pathological mechanisms have yet to be elucidated. Here, we show that genetic deletion of P2rx7 mitigates brain atrophy, tau accumulation and cognitive impairment in PS19 tauopathy mice. Specific deletion of P2rx7 in microglia, but not astrocytes, significantly suppresses tau propagation from the entorhinal cortex to CA1 in the hippocampus, an early event in AD pathology. Single-cell (sc)-RNA sequencing of mouse brains revealed specific P2rx7 expression in microglia, inducing inflammatory changes accompanied by elevated extracellular vesicles (EVs) secretion in PS19 mice. Brain-derived EVs (BDEVs) proteome demonstrated that P2RX7 increases EV cargo loading of tau and mitochondrial molecules in BDEVs from PS19 mice, which was further validated by single-molecule super-resolution. Notably, following the injection of BDEVs isolated from PS19 mice with or without P2rx7 deficiency, the microglial transcriptome of recipient mice revealed enriched DNA-sensing and type II interferon signaling in response to BDEVs from PS19 mice, which was diminished in the group injected with P2rx7-deficient BDEVs. Thus, our results indicate that P2RX7 regulates EV-mediated tau and mitochondrial transfer and inflammatory activation in microglia with increased EV secretion, thereby contributing to tauopathy and neurodegeneration, highlighting the therapeutic potential of targeting the P2RX7-EV axis in AD.
SN  - 0896-6273
SN  - 1097-4199
ER  -