{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Neurobiology, Spencer Fox Eccles School of Medicine, University of Utah, Salt Lake City, USA",
    "University of Utah",
    "Max Planck Institute of Biophysics",
    "Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Frankfurt am Main, Germany",
    "University of Padova",
    "Department of Theoretical Biophysics, Max Planck Institute of Biophysics, Frankfurt am Main, Germany; Institute for Biophysics, Goethe University Frankfurt, Frankfurt am Main, Germany",
    "Harvard Medical School",
    "Department of Biomedical Sciences, University of Padova, Padova, Italy",
    "Department of Neurology, Massachusetts Alzheimer's Disease Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, USA",
    "Department of Neurobiology, Spencer Fox Eccles School of Medicine, University of Utah, Salt Lake City, USA. Electronic address: jason.shepherd@neuro.utah.edu"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 12,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Mitali Tyagi",
      "orcid": "0000-0002-0447-4364"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Eric de Hoog"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Matthew Grega"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Kaelan R. Sullivan",
      "orcid": "0000-0002-6188-3199"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Alan Walker"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Radhika Chadha"
    },
    {
      "affs": [
        0,
        2
      ],
      "name": "Ava Northrop"
    },
    {
      "affs": [
        3,
        4
      ],
      "name": "Balázs Fábián",
      "orcid": "0000-0002-6881-716X"
    },
    {
      "affs": [
        5,
        6
      ],
      "name": "Gerhard Hummer",
      "orcid": "0000-0001-7768-746X"
    },
    {
      "affs": [
        7,
        1
      ],
      "name": "Mónika Fuxreiter",
      "orcid": "0000-0002-4463-6727"
    },
    {
      "affs": [
        8
      ],
      "name": "Bradley T. Hyman",
      "orcid": "0000-0002-7959-9401"
    },
    {
      "affs": [
        9
      ],
      "name": "Jason D. Shepherd",
      "orcid": "0000-0001-7384-8289"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/a0nyxrgacj5xw.bib",
  "cited_by": 19,
  "doi": "10.1016/j.cell.2026.06.008",
  "fulltext_url": null,
  "id": "a0nyxrgacj5xw",
  "issns": [
    "0092-8674",
    "1097-4172"
  ],
  "landing_url": "https://doi.org/10.1016/j.cell.2026.06.008",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2737|Alzheimer's disease research and treatments"
    ],
    [
      "openalex",
      "2804|Alzheimer's disease research and treatments"
    ]
  ],
  "openalex": "W4403701788",
  "pdf_url": null,
  "pmcid": "PMC11526995",
  "pmid": "39484489",
  "published": "2026-06-29",
  "publisher": "Cell Press",
  "ris": "https://research.draconitic.com/paper/a0nyxrgacj5xw.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T13:26:54Z",
      "native_id": "W4403701788",
      "source": "openalex",
      "url": "https://doi.org/10.1016/j.cell.2026.06.008"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2804|Alzheimer's disease research and treatments",
      "subfield": "neuroscience"
    },
    {
      "field": "medicine",
      "origin": "openalex:2737|Alzheimer's disease research and treatments",
      "subfield": "physiology"
    }
  ],
  "title": "Arc mediates intercellular tau transmission via extracellular vesicles",
  "title_text": "Arc mediates intercellular tau transmission via extracellular vesicles",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T13:21:12Z",
  "url": "https://research.draconitic.com/paper/a0nyxrgacj5xw",
  "venue": "Cell",
  "versions": []
}