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Recent studies have shown the potential of anti-tau fragment antibodies in lowering pathological tau levels\n                  <jats:italic>in vitro<\/jats:italic>\n                  and\n                  <jats:italic>in vivo<\/jats:italic>\n                  . Here, we compared the effects of single-chain variable fragments (scFv) derived from the well-characterized monoclonal antibodies PHF1 and MC1. We used adeno-associated virus 1 (AAV1) to deliver scFvs to skeletal muscle cells in eight-week-old P301S tau transgenic mice. We evaluated motor and behavioral functions at 16 and 23 weeks of age and measured misfolded, soluble, oligomeric and insoluble brain tau species. Monotherapy with scFv-MC1 improved motor and behavioral functions more effectively than scFv-PHF1 or combination therapy. Brain glucose metabolism also benefited from scFv-MC1 treatment. Surprisingly, combining scFvs targeting early (MC1) and late (PHF1) tau modifications did not produce additive or synergistic effects. These results confirm that intramuscular AAV1-mediated scFv-MC1 gene therapy holds promise as a potential treatment for Alzheimer\u2019s disease. Our findings also suggest that combining scFvs targeting different tau epitopes may not necessarily enhance efficacy if administered together in a prevention paradigm. Further research is needed to explore whether other antibodies\u2019 combinations and\/or administration schedules could improve the efficacy of scFv-MC1 alone.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Graphical abstract\/eTOC synopsis<\/jats:title>\n                  <jats:p>Katel and colleagues show that peripheral vectorized scFvMC1 (in monotherapy) reduces pathological tau species in tau transgenic mice more efficiently than in combination with scFv-PHF1. The authors observed improved motor and behavioral functions together with increased brain glucose metabolism in scFv-MC1-treated mice.<\/jats:p>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"638144v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.1101\/2025.02.13.638144","type":"posted-content","created":{"date-parts":[[2025,2,18]],"date-time":"2025-02-18T00:35:20Z","timestamp":1739838920000},"source":"Crossref","is-referenced-by-count":1,"title":["AAV-mediated peripheral single chain variable fragments\u2019 administration to reduce cerebral tau in adult P301S transgenic mice: mono- vs combination therapy"],"prefix":"10.64898","author":[{"given":"Sebica","family":"Katel","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia","family":"Cicalo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valeria","family":"Vasciaveo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph","family":"Carrion","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mahadeo","family":"Leann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricio T.","family":"Huerta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philippe","family":"Marambaud","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luca","family":"Giliberto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"d\u2019Abramo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025021905400767000_2025.02.13.638144v1.1","doi-asserted-by":"publisher","DOI":"10.1097\/NEN.0b013e31825018f7"},{"key":"2025021905400767000_2025.02.13.638144v1.2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00308809"},{"key":"2025021905400767000_2025.02.13.638144v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/0197-4580(95)00021-6"},{"key":"2025021905400767000_2025.02.13.638144v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/S0197-4580(97)00062-6"},{"key":"2025021905400767000_2025.02.13.638144v1.5","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.61.3.378"},{"key":"2025021905400767000_2025.02.13.638144v1.6","doi-asserted-by":"publisher","DOI":"10.1002\/mds.20539"},{"key":"2025021905400767000_2025.02.13.638144v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/S0925-4439(00)00037-5"},{"key":"2025021905400767000_2025.02.13.638144v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/31508"},{"key":"2025021905400767000_2025.02.13.638144v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-023-00883-2"},{"key":"2025021905400767000_2025.02.13.638144v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-018-0013-z"},{"key":"2025021905400767000_2025.02.13.638144v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2021.12.002"},{"key":"2025021905400767000_2025.02.13.638144v1.12","doi-asserted-by":"crossref","unstructured":"DeVos SL , Miller RL , Schoch KM , Holmes BB , Kebodeaux CS , Wegener AJ , et al. 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