{
  "abstract": "Pathological tau aggregates drive neuronal dysfunction in Alzheimer's disease (AD) and related tauopathies, yet no approved therapy eliminates existing tau neurofibrillary tangles. Here, we report the development of a coumarin-based small-molecule series that disaggregates tau fibrils and oligomers through a stacking-driven co-assembly mechanism. Structure-activity relationships identified PT-13 as a lead compound that inhibits tau seeding by AD brain-derived matter and reduces aggregate burden measured across both fibrillar and oligomeric tau species. Mechanistic studies demonstrate that disaggregation does not generate soluble oligomeric intermediates, addressing a central question in the field. PT-13 is brain-penetrant and well tolerated in vivo. In a tauopathy mouse model, PT-13 treatment reduces tau pathology while preserving behavioral function, proteasome capacity, and synaptic integrity. These findings establish small-molecule tau disaggregation as a viable therapeutic strategy and provide a molecular framework for the design of aggregate-directed therapeutics in neurodegeneration.",
  "abstract_shown": true,
  "affiliations": [
    "University of Southern California"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "name": "N. Mostowfi"
    },
    {
      "name": "R. Foreman"
    },
    {
      "name": "J. Wang"
    },
    {
      "name": "R. Khoury"
    },
    {
      "name": "A. Albanese"
    },
    {
      "name": "Q. L. Ma"
    },
    {
      "name": "W. Cohn"
    },
    {
      "name": "G. Petzinger"
    },
    {
      "name": "M. W. Jakowec"
    },
    {
      "name": "S. Ahmed"
    },
    {
      "affs": [
        0
      ],
      "name": "P. M. Seidler"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/7pzznjpbe6a1p.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.06.09.731185",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.06.09.731185v2.full",
  "id": "7pzznjpbe6a1p",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.06.09.731185v2",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "neuroscience"
    ],
    [
      "openalex",
      "2737|Alzheimer's disease research and treatments"
    ]
  ],
  "openalex": "W7164526001",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.06.09.731185v2.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-06-09",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/7pzznjpbe6a1p.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:29Z",
      "native_id": "10.64898/2026.06.09.731185",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.06.09.731185v2"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:neuroscience",
      "subfield": "neuroscience"
    }
  ],
  "title": "Tau Disaggregation by a CNS-Permeable Small Molecule Reduces Fibril and Oligomer Burden and Preserves Proteostasis and Behavior",
  "title_text": "Tau Disaggregation by a CNS-Permeable Small Molecule Reduces Fibril and Oligomer Burden and Preserves Proteostasis and Behavior",
  "type": "preprint",
  "updated_at": "2026-10-30T12:18:29Z",
  "url": "https://research.draconitic.com/paper/7pzznjpbe6a1p",
  "venue": "bioRxiv",
  "versions": []
}