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Peer-reviewedCC BYCell

Arc mediates intercellular tau transmission via extracellular vesicles

  • Mitali Tyagi1,2
  • Eric de Hoog1,2
  • Matthew Grega1,2
  • Kaelan R. Sullivan1,2
  • Alan Walker1,2
  • Radhika Chadha1,2
  • Ava Northrop1,3
  • Balázs Fábián4,5
  • Gerhard Hummer6,7
  • Mónika Fuxreiter8,2
  • Bradley T. Hyman9
  • Jason D. Shepherd10
10 affiliations
  1. 1Department of Neurobiology, Spencer Fox Eccles School of Medicine, University of Utah, Salt Lake City, USA
  2. 2University of Utah
  3. 3Max Planck Institute of Biophysics
  4. 4Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Frankfurt am Main, Germany
  5. 5University of Padova
  6. 6Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Frankfurt am Main, Germany; Institute for Biophysics, Goethe University Frankfurt, Frankfurt am Main, Germany
  7. 7Harvard Medical School
  8. 8Department of Biomedical Sciences, University of Padova, Padova, Italy
  9. 9Department of Neurology, Massachusetts Alzheimer's Disease Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, USA
  10. 10Department of Neurobiology, Spencer Fox Eccles School of Medicine, University of Utah, Salt Lake City, USA. Electronic address: [email protected]
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Abstract

Intracellular neurofibrillary tangles that consist of misfolded tau protein 1 cause neurodegeneration in Alzheimer’s disease (AD) and frontotemporal dementia (FTD). Tau pathology spreads cell-to-cell 2 but the exact mechanisms of tau release and intercellular transmission remain poorly defined. Tau is released from neurons as free protein or in extracellular vesicles (EVs) 3–5 but the role of these different release mechanisms in intercellular tau transmission is unclear. Here, we show that the neuronal gene Arc is critical for packaging tau into EVs. Brain EVs purified from human tau (hTau) transgenic rTg4510 mice (rTg WT ) contain high levels of hTau that are capable of seeding tau pathology. In contrast, EVs purified from rTg WT crossed with Arc knock-out mice (rTg Arc KO ) have significantly less hTau and cannot seed tau aggregation. Arc facilitates the release of hTau in EVs produced via the I-BAR protein IRSp53, but not free tau. Arc protein directly binds hTau to form a fuzzy complex that we identified in both mouse and human brain tissue. We find that pathological intracellular hTau accumulates in neurons in rTg Arc KO mice, which correlates with accelerated neuron loss in the hippocampus. Finally, we find that intercellular tau transmission is significantly abrogated in Arc KO mice. We conclude that Arc-dependent release of tau in EVs plays a significant role in intracellular tau elimination and intercellular tau transmission.

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Cite

BibTeXRIS
BibTeX
@article{tyagi2026mediates,
  title = {{Arc mediates intercellular tau transmission via extracellular vesicles}},
  author = {Mitali Tyagi and Eric de Hoog and Matthew Grega and Kaelan R. Sullivan and Alan Walker and Radhika Chadha and Ava Northrop and Balázs Fábián and Gerhard Hummer and Mónika Fuxreiter and Bradley T. Hyman and Jason D. Shepherd},
  journal = {Cell},
  year = {2026},
  month = jun,
  doi = {10.1016/j.cell.2026.06.008},
  url = {https://doi.org/10.1016/j.cell.2026.06.008},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Arc mediates intercellular tau transmission via extracellular vesicles
AU  - Mitali Tyagi
AU  - Eric de Hoog
AU  - Matthew Grega
AU  - Kaelan R. Sullivan
AU  - Alan Walker
AU  - Radhika Chadha
AU  - Ava Northrop
AU  - Balázs Fábián
AU  - Gerhard Hummer
AU  - Mónika Fuxreiter
AU  - Bradley T. Hyman
AU  - Jason D. Shepherd
PY  - 2026
DA  - 2026/06/29
JO  - Cell
DO  - 10.1016/j.cell.2026.06.008
UR  - https://doi.org/10.1016/j.cell.2026.06.008
AB  - Intracellular neurofibrillary tangles that consist of misfolded tau protein 1 cause neurodegeneration in Alzheimer’s disease (AD) and frontotemporal dementia (FTD). Tau pathology spreads cell-to-cell 2 but the exact mechanisms of tau release and intercellular transmission remain poorly defined. Tau is released from neurons as free protein or in extracellular vesicles (EVs) 3–5 but the role of these different release mechanisms in intercellular tau transmission is unclear. Here, we show that the neuronal gene Arc is critical for packaging tau into EVs. Brain EVs purified from human tau (hTau) transgenic rTg4510 mice (rTg WT ) contain high levels of hTau that are capable of seeding tau pathology. In contrast, EVs purified from rTg WT crossed with Arc knock-out mice (rTg Arc KO ) have significantly less hTau and cannot seed tau aggregation. Arc facilitates the release of hTau in EVs produced via the I-BAR protein IRSp53, but not free tau. Arc protein directly binds hTau to form a fuzzy complex that we identified in both mouse and human brain tissue. We find that pathological intracellular hTau accumulates in neurons in rTg Arc KO mice, which correlates with accelerated neuron loss in the hippocampus. Finally, we find that intercellular tau transmission is significantly abrogated in Arc KO mice. We conclude that Arc-dependent release of tau in EVs plays a significant role in intracellular tau elimination and intercellular tau transmission.
SN  - 0092-8674
SN  - 1097-4172
ER  -