{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T05:04:55Z","timestamp":1789621495629,"version":"build-2803163510"},"reference-count":43,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100017510","name":"UK Dementia Research Institute","doi-asserted-by":"publisher","award":["DRI\u2010PRO202332"],"award-info":[{"award-number":["DRI\u2010PRO202332"]}],"id":[{"id":"10.13039\/501100017510","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000923","name":"Australian Research Council","doi-asserted-by":"publisher","award":["DE240100707"],"award-info":[{"award-number":["DE240100707"]}],"id":[{"id":"10.13039\/501100000923","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/V036947\/1"],"award-info":[{"award-number":["MR\/V036947\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Tau aggregation is a central pathological feature of Alzheimer's disease, yet how different forms of tau\u2014ranging from monomers to small soluble aggregates and mature fibrils\u2014interact with the cellular environment remains poorly understood. Here, we combine immunoaffinity proteomics with single\u2010molecule techniques and super\u2010resolution microscopy to systematically map the tau interactome across defined aggregation states, spanning monomeric tau, nanoscopic soluble aggregates, and fibrillar species. Using post\u2010mortem Alzheimer's disease brain tissue, we identify distinct functional modules associated with different aggregation states: while proteostasis factors and immune\u2010related proteins preferentially associate with nanoscopic aggregates (oligomers), cytoskeletal, metabolic, and RNA\u2010binding proteins are enriched for mature fibrillar tau. Single\u2010molecule microscopy directly confirms this conformation\u2010dependent recruitment for key interactors including Hsp70\u20102, ENO1, hnRNPA1, APP, EAAT4, and ubiquitin. A primary\u2010neuron system with accelerated tau aggregation is used to model these findings in a controlled system, showing striking similarities to the brain samples. Finally, pseudotime analysis reconstructs a progressive remodelling of the tau interactome across disease progression, revealing stage\u2010specific pathway vulnerabilities. Together, these results establish a temporally resolved framework for tau pathology shaped by protein interactions and identify potential therapeutic intervention points for investigation across stages of disease.<\/jats:p>","DOI":"10.1002\/advs.77822","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T04:47:31Z","timestamp":1789620451000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Temporal Trajectories of the Tau Aggregate Interactome Reveal Stage\u2010Specific Vulnerabilities in Alzheimer's Disease"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-8443-4469","authenticated-orcid":false,"given":"Dorothea","family":"B\u00f6ken","sequence":"first","affiliation":[{"name":"Yusuf Hamied Department of Chemistry University of Cambridge  Cambridge UK"},{"name":"UK Dementia Research Institute University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2499-7740","authenticated-orcid":false,"given":"Paula Beltran","family":"Lobo","sequence":"additional","affiliation":[{"name":"Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute King's College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunzhao","family":"Wu","sequence":"additional","affiliation":[{"name":"Yusuf Hamied Department of Chemistry University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyla A.","family":"Rowe","sequence":"additional","affiliation":[{"name":"Centre For Neuroscience, Surgery and Trauma, The Blizard Institute Queen Mary University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0060-5806","authenticated-orcid":false,"given":"Emre","family":"Fertan","sequence":"additional","affiliation":[{"name":"Yusuf Hamied Department of Chemistry University of Cambridge  Cambridge UK"},{"name":"UK Dementia Research Institute University of Cambridge  Cambridge UK"},{"name":"Department of Clinical Neurosciences University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7969-5084","authenticated-orcid":false,"given":"Cara L.","family":"Croft","sequence":"additional","affiliation":[{"name":"Centre For Neuroscience, Surgery and Trauma, The Blizard Institute Queen Mary University of London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2287-1582","authenticated-orcid":false,"given":"Maria","family":"Jimenez\u2010Sanchez","sequence":"additional","affiliation":[{"name":"Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute King's College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dezerae","family":"Cox","sequence":"additional","affiliation":[{"name":"Yusuf Hamied Department of Chemistry University of Cambridge  Cambridge UK"},{"name":"UK Dementia Research Institute University of Cambridge  Cambridge UK"},{"name":"Molecular Horizons, School of Sciences University of Wollongong  Wollongong New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7116-6954","authenticated-orcid":false,"given":"David","family":"Klenerman","sequence":"additional","affiliation":[{"name":"Yusuf Hamied Department of Chemistry University of Cambridge  Cambridge UK"},{"name":"UK Dementia Research Institute University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"crossref","DOI":"10.3390\/ijms232112841","article-title":"Phosphorylated Tau in Alzheimer's Disease and Other Tauopathies","volume":"23","author":"Rawat P.","year":"2022","journal-title":"International Journal of Molecular Sciences"},{"key":"e_1_2_10_3_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/ncomms15295","article-title":"Tau Association with Synaptic Vesicles Causes Presynaptic Dysfunction","volume":"8","author":"Zhou L.","year":"2017","journal-title":"Nature Communications"},{"key":"e_1_2_10_4_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.brainres.2024.149202","article-title":"Proteostasis Disruption and Senescence in Alzheimer's Disease Pathways to Neurodegeneration","volume":"1845","author":"Thapa R.","year":"2024","journal-title":"Brain Research"},{"key":"e_1_2_10_5_1","doi-asserted-by":"crossref","DOI":"10.3389\/fcell.2021.707268","article-title":"Possible Mechanisms of Tau Spread and Toxicity in Alzheimer's Disease","volume":"9","author":"Zhang H.","year":"2021","journal-title":"Frontiers in Cell and Developmental Biology"},{"key":"e_1_2_10_6_1","doi-asserted-by":"crossref","first-page":"9207","DOI":"10.3390\/ijms22179207","article-title":"Tau Protein Interaction Partners and Their Roles in Alzheimer's Disease and Other Tauopathies","volume":"22","author":"Sinsky J.","year":"2021","journal-title":"International Journal of Molecular Sciences"},{"key":"e_1_2_10_7_1","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1007\/s00401-020-02261-4","article-title":"The Proteome of Granulovacuolar Degeneration and Neurofibrillary Tangles in Alzheimer's Disease","volume":"141","author":"Hondius D. 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A.","year":"2011","journal-title":"Molecular Neurodegeneration"},{"key":"e_1_2_10_11_1","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1038\/s41593-022-01191-6","article-title":"Bassoon Contributes to Tau\u2010Seed Propagation and Neurotoxicity","volume":"25","author":"Martinez P.","year":"2022","journal-title":"Nature Neuroscience"},{"key":"e_1_2_10_12_1","doi-asserted-by":"crossref","first-page":"2803","DOI":"10.1093\/brain\/awaa223","article-title":"Phosphorylated Tau Interactome in the Human Alzheimer's Disease Brain","volume":"143","author":"Drummond E.","year":"2020","journal-title":"Brain"},{"key":"e_1_2_10_13_1","doi-asserted-by":"crossref","DOI":"10.1002\/cbic.202400877","article-title":"Detecting the Undetectable: Advances in Methods for Identifying Small Tau Aggregates in Neurodegenerative Diseases","volume":"26","author":"B\u00f6ken D.","year":"2025","journal-title":"ChemBioChem"},{"key":"e_1_2_10_14_1","doi-asserted-by":"crossref","DOI":"10.1002\/ange.202317756","article-title":"Single\u2010Molecule Characterization and Super\u2010Resolution Imaging of Alzheimer's Disease\u2010Relevant Tau Aggregates in Human Samples","volume":"136","author":"B\u00f6ken D.","year":"2024","journal-title":"Angewandte Chemie"},{"key":"e_1_2_10_15_1","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1084\/jem.20182184","article-title":"RAAV\u2010Based Brain Slice Culture Models of Alzheimer's and Parkinson's Disease Inclusion Pathologies","volume":"216","author":"Croft C. L.","year":"2019","journal-title":"Journal of Experimental Medicine"},{"key":"e_1_2_10_16_1","doi-asserted-by":"crossref","first-page":"4260","DOI":"10.1523\/JNEUROSCI.3192-13.2014","article-title":"Passive Immunization with Tau Oligomer Monoclonal Antibody Reverses Tauopathy Phenotypes Without Affecting Hyperphosphorylated Neurofibrillary Tangles","volume":"34","author":"Castillo\u2010Carranza D. 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A.","year":"2022","journal-title":"Biomedical Reports"},{"key":"e_1_2_10_34_1","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1021\/acschembio.7b01039","article-title":"Hsp70 Inhibits the Nucleation and Elongation of Tau and Sequesters Tau Aggregates With High Affinity","volume":"13","author":"Kundel F.","year":"2018","journal-title":"ACS Chemical Biology"},{"key":"e_1_2_10_35_1","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1016\/j.jmb.2019.08.021","article-title":"N\u2010Terminal Ubiquitination of Amyloidogenic Proteins Triggers Removal of Their Oligomers by the Proteasome Holoenzyme","volume":"432","author":"Ye Y.","year":"2020","journal-title":"Journal of Molecular Biology"},{"key":"e_1_2_10_36_1","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/s13024-025-00817-0","article-title":"Probe\u2010Dependent Proximity Profiling (ProPPr) Uncovers Similarities and Differences in Phospho\u2010Tau\u2010Associated Proteomes between Tauopathies","volume":"20","author":"Morderer D.","year":"2025","journal-title":"Molecular Neurodegeneration"},{"key":"e_1_2_10_37_1","doi-asserted-by":"crossref","first-page":"2181","DOI":"10.7150\/ijbs.57078","article-title":"Interaction Between A\u03b2 and Tau in the Pathogenesis of Alzheimer's Disease","volume":"17","author":"Zhang H.","year":"2021","journal-title":"International Journal of Biological Sciences"},{"key":"e_1_2_10_38_1","doi-asserted-by":"crossref","first-page":"D543","DOI":"10.1093\/nar\/gkae1011","article-title":"The PRIDE Database at 20 Years: 2025 Update","volume":"53","author":"Perez\u2010Riverol Y.","year":"2025","journal-title":"Nucleic Acids Research"},{"key":"e_1_2_10_39_1","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/s13024-020-00361-z","article-title":"Utilizing Minimally Purified Secreted RAAV for Rapid and Cost\u2010Effective Manipulation of Gene Expression in the CNS","volume":"15","author":"Goodwin M. 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D.","year":"2014","journal-title":"Journal of Visualized Experiments\u00a0: JoVE"},{"key":"e_1_2_10_43_1","article-title":"Quantitative Profiling of Nanoscopic Protein Aggregates Reveals Specific Fingerprint of TDP\u201043\u2010Positive Assemblies in Motor Neuron Disease","volume":"12","author":"Cox D.","year":"2025","journal-title":"Advanced Science"},{"key":"e_1_2_10_44_1","doi-asserted-by":"crossref","first-page":"1992","DOI":"10.1038\/s41467-022-29661-2","article-title":"Hidden Information on Protein Function in Censuses of Proteome Foldedness","volume":"13","author":"Cox D.","year":"2022","journal-title":"Nature Communications"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.77822","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/advs.77822","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.77822","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T04:47:44Z","timestamp":1789620464000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.77822"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,16]]},"references-count":43,"alternative-id":["10.1002\/advs.77822"],"URL":"https:\/\/doi.org\/10.1002\/advs.77822","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,16]]},"assertion":[{"value":"2026-01-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-08","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-16","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e77822"}}