{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T13:07:44Z","timestamp":1778936864725,"version":"3.51.4"},"posted":{"date-parts":[[2024,11,4]]},"group-title":"Neuroscience","reference-count":77,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,11,4]],"date-time":"2024-11-04T00:00:00Z","timestamp":1730678400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,13]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  The lack of models in which ageing and amyloid-\u03b2 (A\u03b2) initiate neurofibrillary tau tangles, independent of\n                  <jats:italic>MAPT<\/jats:italic>\n                  mutations, limits mechanistic insights into Alzheimer\u2019s disease. Here, we characterise NLFTau\n                  <jats:sup>m\/h<\/jats:sup>\n                  , a novel mouse model that recapitulates the gradual transition from A\u03b2 accumulation to tau pathology by 24 months. We show that combined effects of ageing, A\u03b2, and human tau expression promote tau pathology. However, either A\u03b2 plaques or human tau alone can initiate tau pathology, but only in even older mice. This may be exacerbated by increased neuronal vulnerability across all genotypes with age. Moreover, multi-omic analyses reveal that human tau can induce early alterations in mitochondrial and synaptic pathways, priming this latent vulnerability preceding tau pathology. Together, this suggests that ageing and other interacting triggers accelerate the onset of tau pathology. This opens possibilities for translatable testing of improved therapies for Alzheimer\u2019s disease, breaking the link between A\u03b2 and tau pathologies.\n                <\/jats:p>","DOI":"10.1101\/2024.11.04.621900","type":"posted-content","created":{"date-parts":[[2024,11,4]],"date-time":"2024-11-04T21:15:32Z","timestamp":1730754932000},"source":"Crossref","is-referenced-by-count":1,"title":["Age- and amyloid-\u03b2-dependent initiation of neurofibrillary tau tangles: NLFTau\n                  <sup>m\/h<\/sup>\n                  , an improved mouse model of Alzheimer\u2019s disease without mutations in\n                  <i>MAPT<\/i>"],"prefix":"10.64898","author":[{"given":"Sneha","family":"Desai","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, United Kingdom"},{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, M\u00f6lndal, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiongqiao","family":"La","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aya","family":"Balbaa","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Camporesi","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, M\u00f6lndal, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gunnar","family":"Brinkmalm","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, M\u00f6lndal, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kritika","family":"Goyal","sequence":"additional","affiliation":[{"name":"Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, United States of America"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Argyro","family":"Alatza","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease, University College London, Queen Square Institute of Neurology, London, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jack I.","family":"Wood","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, United Kingdom"},{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, M\u00f6lndal, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takshashila","family":"Tripathi","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sumi","family":"Bez","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute, University College London, Gower Street, London, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nazar","family":"Stasyuk","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haady B.","family":"Hajar","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takashi","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takaomi C.","family":"Saido","sequence":"additional","affiliation":[{"name":"Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako, Saitama, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Henrik","family":"Zetterberg","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, M\u00f6lndal, Sweden"},{"name":"Department of Neurodegenerative Disease, University College London, Queen Square Institute of Neurology, London, United Kingdom"},{"name":"UK Dementia Research Institute, University College London, Gower Street, London, United Kingdom"},{"name":"Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, M\u00f6lndal, Sweden"},{"name":"Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Hardy","sequence":"additional","affiliation":[{"name":"Department of Neurodegenerative Disease, University College London, Queen Square Institute of Neurology, London, United Kingdom"},{"name":"UK Dementia Research Institute, University College London, Gower Street, London, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey N.","family":"Savas","sequence":"additional","affiliation":[{"name":"Department of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, United States of America"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dervis A.","family":"Salih","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute, University College London, Gower Street, London, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Damian M.","family":"Cummings","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, United Kingdom"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J\u00f6rg","family":"Hanrieder","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The 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