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Adv."],"published-print":{"date-parts":[[2026,7,31]]},"abstract":"<jats:p>\n                    The accumulation of pathological four-repeat (4R) tau is central to several frontotemporal dementia (FTD) subtypes, but human neuronal models amenable to high-throughput screening of 4R tau\u2013targeting therapies remain very limited. To address this, we developed induced pluripotent stem cell (iPSC)\u2013derived i\n                    <jats:sup>3<\/jats:sup>\n                    Neuron (i\n                    <jats:sup>3<\/jats:sup>\n                    N) lines expressing &gt;75% 4R tau, driven by FTD splice-shifting mutations (Ser\n                    <jats:sup>305<\/jats:sup>\n                    Asn; S305N or S305N\/IVS10\u00a0+\u00a03). These neurons develop hyperphosphorylated tau and demonstrate somatodendritic mislocalization. These i\n                    <jats:sup>3<\/jats:sup>\n                    N neurons develop endogenous seed-competent tau and present pentameric formyl thiophene acetic acid\u2013(pFTAA)-positive tau assemblies after 28 days in culture. For scalable screening, we CRISPR-engineered an HiBiT luminescence tag at the endogenous\n                    <jats:italic toggle=\"yes\">MAPT<\/jats:italic>\n                    locus into the S305N\/IVS10\u00a0+\u00a03 iPSC line, enabling precise quantification of tau levels and pharmacological responses. The model responded predictably to compounds affecting tau clearance, demonstrating its suitability for drug discovery. Overall, this i\n                    <jats:sup>3<\/jats:sup>\n                    N platform recapitulates key features of 4R tauopathy and provides a robust system to identify therapeutic modulators of pathological tau.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aeg1445","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T17:58:34Z","timestamp":1785520714000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Scalable human neuronal models of tauopathy producing endogenous seed-competent 4R tau"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4643-2584","authenticated-orcid":true,"given":"Eliona","family":"Tsefou","sequence":"first","affiliation":[{"name":"UK Dementia Research Institute, University College London, London, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8971-5103","authenticated-orcid":true,"given":"Sumi","family":"Bez","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute, University College London, London, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy J. 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London, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7488-5898","authenticated-orcid":true,"given":"Daria","family":"Gavriouchkina","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute, University College London, London, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7447-1476","authenticated-orcid":true,"given":"Emir","family":"Turkes","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute, University College London, London, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7017-4583","authenticated-orcid":true,"given":"Samuel","family":"Crawford","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, 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