{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T22:24:12Z","timestamp":1768515852244,"version":"3.49.0"},"posted":{"date-parts":[[2024,9,2]]},"group-title":"Biochemistry","reference-count":64,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2024,9,2]],"date-time":"2024-09-02T00:00:00Z","timestamp":1725235200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,9,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Aggregation of microtubule-associated protein tau (MAPT\/tau) into conformationally distinct fibrils underpins neurodegenerative tauopathies. Fluorescent probes (fluoroprobes), such as thioflavin T (ThT), have been essential tools for studying tau aggregation; however, most of them do not discriminate between amyloid fibril conformations (polymorphs). This gap is due, in part, to a lack of high-throughput methods for screening large, diverse chemical collections. Here, we leverage advances in protein adaptive differential scanning fluorimetry (paDSF) to screen the Aurora collection of 300+ fluorescent dyes against multiple synthetic tau fibril polymorphs. This screen, coupled with orthogonal secondary assays, revealed pan-fibril binding chemotypes, as well as fluoroprobes selective for subsets of fibrils. One fluoroprobe recognized tau pathology in\n                  <jats:italic>ex vivo<\/jats:italic>\n                  brain slices from Alzheimer\u2019s disease patients. We propose that these scaffolds represent entry points for development of selective fibril ligands and, more broadly, that high throughput, fluorescence-based dye screening is a platform for their discovery.\n                <\/jats:p>","DOI":"10.1101\/2024.09.02.610853","type":"posted-content","created":{"date-parts":[[2024,9,3]],"date-time":"2024-09-03T00:20:10Z","timestamp":1725322810000},"source":"Crossref","is-referenced-by-count":0,"title":["Methods for high throughput discovery of fluoroprobes that recognize tau fibril polymorphs"],"prefix":"10.64898","author":[{"given":"Emma C.","family":"Carroll","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyunjun","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia G.","family":"Jones","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abby","family":"Oehler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annemarie F.","family":"Charvat","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelly M.","family":"Montgomery","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anthony","family":"Yung","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zoe","family":"Millbern","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nelson R.","family":"Vinueza","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William F.","family":"DeGrado","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel A.","family":"Mordes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlo","family":"Condello","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6125-3154","authenticated-orcid":false,"given":"Jason E.","family":"Gestwicki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024090416050878000_2024.09.02.610853v1.1","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-021-00476-x"},{"key":"2024090416050878000_2024.09.02.610853v1.2","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1039\/D1CS00127B","article-title":"Revisiting the grammar of tau aggregation and pathology formation: How new insights from brain pathology are shaping how we study and target tauopathies","volume":"51","year":"2022","journal-title":"Chemical Society reviews"},{"key":"2024090416050878000_2024.09.02.610853v1.3","doi-asserted-by":"crossref","unstructured":"Chang, C. W. ; Shao, E. ; Mucke, L . (2021) Tau: Enabler of diverse brain disorders and target of rapidly evolving therapeutic strategies, Science 371.","DOI":"10.1126\/science.abb8255"},{"key":"2024090416050878000_2024.09.02.610853v1.4","doi-asserted-by":"publisher","DOI":"10.1007\/BF00687747"},{"key":"2024090416050878000_2024.09.02.610853v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.sbi.2020.05.011"},{"key":"2024090416050878000_2024.09.02.610853v1.6","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-018-1914-z"},{"key":"2024090416050878000_2024.09.02.610853v1.7","doi-asserted-by":"publisher","DOI":"10.1021\/bi980537d"},{"key":"2024090416050878000_2024.09.02.610853v1.8","doi-asserted-by":"publisher","DOI":"10.1002\/pro.5560020312"},{"key":"2024090416050878000_2024.09.02.610853v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbapap.2010.04.001"},{"key":"2024090416050878000_2024.09.02.610853v1.10","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1002867107"},{"key":"2024090416050878000_2024.09.02.610853v1.11","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M412056200"},{"key":"2024090416050878000_2024.09.02.610853v1.12","doi-asserted-by":"publisher","DOI":"10.1021\/ar300053p"},{"key":"2024090416050878000_2024.09.02.610853v1.13","doi-asserted-by":"publisher","DOI":"10.1177\/37.8.2666510"},{"key":"2024090416050878000_2024.09.02.610853v1.14","doi-asserted-by":"publisher","DOI":"10.1111\/j.1747-0285.2007.00557.x"},{"key":"2024090416050878000_2024.09.02.610853v1.15","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.200500550"},{"key":"2024090416050878000_2024.09.02.610853v1.16","doi-asserted-by":"publisher","DOI":"10.1021\/ja405239v"},{"key":"2024090416050878000_2024.09.02.610853v1.17","doi-asserted-by":"crossref","first-page":"12254","DOI":"10.1021\/acs.chemrev.3c00494","article-title":"Advanced techniques for detecting protein misfolding and aggregation in cellular environments","volume":"123","year":"2023","journal-title":"Chem Rev"},{"key":"2024090416050878000_2024.09.02.610853v1.18","doi-asserted-by":"publisher","DOI":"10.1021\/acs.biochem.5b00309"},{"key":"2024090416050878000_2024.09.02.610853v1.19","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.3c03749"},{"key":"2024090416050878000_2024.09.02.610853v1.20","doi-asserted-by":"crossref","first-page":"1354","DOI":"10.1039\/D3CS00518F","article-title":"A closer look at amyloid ligands, and what they tell us about protein aggregates","volume":"53","year":"2024","journal-title":"Chemical Society reviews"},{"key":"2024090416050878000_2024.09.02.610853v1.21","doi-asserted-by":"crossref","unstructured":"Rauch, J. 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(2023) Tau p301l mutation promotes core 4r tauopathy fibril fold through near-surface water structuring and conformational rearrangement, bioRxiv.","DOI":"10.1101\/2023.11.28.568818"},{"key":"2024090416050878000_2024.09.02.610853v1.29","doi-asserted-by":"publisher","DOI":"10.1021\/jacs.2c08004"},{"key":"2024090416050878000_2024.09.02.610853v1.30","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1021\/acs.biochem.2c00111","article-title":"In vitro tau aggregation inducer molecules influence the effects of mapt mutations on aggregation dynamics","volume":"61","year":"2022","journal-title":"Biochemistry"},{"key":"2024090416050878000_2024.09.02.610853v1.31","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2119952119"},{"key":"2024090416050878000_2024.09.02.610853v1.32","doi-asserted-by":"publisher","DOI":"10.1002\/bip.10485"},{"key":"2024090416050878000_2024.09.02.610853v1.33","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1021\/acssensors.3c01334","article-title":"A coumarin-based array for the discrimination of amyloids","volume":"9","year":"2024","journal-title":"ACS Sens"},{"key":"2024090416050878000_2024.09.02.610853v1.34","doi-asserted-by":"crossref","unstructured":"Lovestam, S. ; Koh, F. 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