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Increased syntaxin-6 protein levels are also causally associated with Alzheimer\u2019s disease, suggesting it may have shared roles across multiple neurodegenerative diseases. However, no study has validated its functional role in tauopathies. To validate a role for syntaxin-6 in tauopathy pathogenesis, we knocked out syntaxin-6 in humanised P301S tauopathy mice. Mice underwent longitudinal rotarod testing, gait analysis, frailty and weight assessment, with neuropathological, biochemical and pathological analyses at 3 and 5\u00a0months.\n                    <jats:italic>Stx6<\/jats:italic>\n                    <jats:sup>+\/+<\/jats:sup>\n                    ;h\n                    <jats:italic>Tau<\/jats:italic>\n                    <jats:sup>P301S\/P301S<\/jats:sup>\n                    mice showed motor impairment from 1\u00a0month of age, which was partially rescued by syntaxin-6 knockout from months 1 to 4, with additional protection of gait at 5.5\u00a0months. Physiologically, syntaxin-6 knockout exerted a protective effect on weight trajectories and measures of frailty. Reduced neurodegeneration in the superficial cortex was observed at 3\u00a0months, as well as higher synaptic coverage at 5\u00a0months of age, supporting preserved neuropathological measures related to function. We further observed localised increases in tau pathology in the spinal cord and defined brain regions in young\n                    <jats:italic>Stx6<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    <jats:italic>;<\/jats:italic>\n                    h\n                    <jats:italic>Tau<\/jats:italic>\n                    <jats:sup>P301S\/P301S<\/jats:sup>\n                    mice, despite total tau levels being comparable, in keeping with altered trafficking of pathological tau species with syntaxin-6 knockout. Despite a partial, early phenotypic rescue of functional measures, terminal endpoint comparisons were confounded by a 20% weight loss culling rule, as knockout mice maintained higher absolute weight. Taken together, this study functionally validates a role for syntaxin-6 in tauopathy pathogenesis, with syntaxin-6 knockout resulting in an early protective effect on multiple disease-relevant phenotypes in a humanised tauopathy model.\n                  <\/jats:p>","DOI":"10.1007\/s00401-026-03009-2","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T12:06:12Z","timestamp":1776859572000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Modification of early behavioural, physiological and neuropathological endpoints by syntaxin-6 knockout in a humanised P301S transgenic model of tauopathy"],"prefix":"10.1007","volume":"151","author":[{"given":"Elizabeth","family":"Hill","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacqueline","family":"Linehan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Farmer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatiana","family":"Jakubcova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shyma","family":"Hamdan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"Tomlinson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Purro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fabio","family":"Argentina","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emma","family":"Jones","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas","family":"Kaye","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Craig","family":"Fitzhugh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rohan","family":"de Silva","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sebastian","family":"Brandner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Collinge","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas J.","family":"Cunningham","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon","family":"Mead","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,4,22]]},"reference":[{"issue":"21","key":"3009_CR1","doi-asserted-by":"publisher","first-page":"9340","DOI":"10.1523\/JNEUROSCI.22-21-09340.2002","volume":"22","author":"B Allen","year":"2002","unstructured":"Allen B, Ingram E, Takao M, Smith MJ, Jakes R, Virdee K et al (2002) Abundant tau filaments and nonapoptotic neurodegeneration in transgenic mice expressing human P301S tau protein. 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