{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:27:59Z","timestamp":1785414479487,"version":"3.56.0"},"posted":{"date-parts":[[2025,9,25]]},"group-title":"Neuroscience","reference-count":46,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T00:00:00Z","timestamp":1758758400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"id":[{"id":"https:\/\/ror.org\/05nzwyq50","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Massachusetts Alzheimer\u2019s disease Research Center","award":["P30AG062421"],"award-info":[{"award-number":["P30AG062421"]}]},{"name":"The Toffler Foundation"},{"id":[{"id":"https:\/\/ror.org\/05ewr7t48","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/003q4qk22","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/02wedp412","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,2,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>In Alzheimer\u2019s disease, both classical neurofibrillary tangles, and diffusible, aqueous soluble (High Molecular Weight, or HMW) species are able to support templated misfolding. How these tau proteoforms relate is uncertain. Using sequential size exclusion and anion exchange chromatography, we fractionated the HMW tau population and found both seed competent, and seed not competent proteoforms. Super resolution, atomic force, and immunogold electron microscopy confirmed that the size and conformation of both bioactive and non-bioactive tau proteoforms are similar, with dimers, trimers, and tetramers predominating. The presence of surface phosphorylation correlates with seeding capacity. Bioactive tau at fMol concentrations can induce seeding in a reporter cell. The soluble bioactive species support aggregation of a truncated repeat domain tau construct into thioflavin T positive fibrils and retain seeding activity over serial amplification in vitro and in cellulo, whereas non-bioactive oligomeric species do not. Together, these findings indicate that oligomeric assembly is required but not sufficient for seeding; instead, specific biochemical attributes of a rare oligomeric tau subset confer self-propagating, prion-like templated misfolding.<\/jats:p>","DOI":"10.1101\/2025.09.24.678227","type":"posted-content","created":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T18:30:33Z","timestamp":1758825033000},"source":"Crossref","is-referenced-by-count":0,"title":["Rare bioactive diffusible tau species from Alzheimer brain support both templated misfolding and fibril formation"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1946-8677","authenticated-orcid":false,"given":"No\u00e9","family":"Quittot","sequence":"first","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital, Boston, MA, USA"},{"name":"Harvard Medical School, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dhanush","family":"Sivasankaran","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital, Boston, MA, USA"},{"name":"Harvard Medical School, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8443-4469","authenticated-orcid":false,"given":"Dorothea","family":"B\u00f6ken","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute at the University of Cambridge, Cambridge, UK"},{"name":"Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, Northeastern University, Boston, MA, USA"},{"name":"Department of Physics, Northeastern University, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua E.","family":"Chun","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital, Boston, MA, USA"},{"name":"Harvard Medical School, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne E.","family":"Wiedmer","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital, Boston, MA, USA"},{"name":"Harvard Medical School, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Derosla","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital, Boston, MA, USA"},{"name":"Harvard Medical School, Cambridge, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana B. 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