Carroll, E.C., Yang, H., Powell, W.C. et al. (15 more authors) (2025) High-throughput discovery of fluoroprobes that recognize amyloid fibril polymorphs. Nature Chemistry. ISSN: 1755-4330
Abstract
Aggregation of microtubule-associated protein tau into conformationally distinct fibrils underpins neurodegenerative tauopathies. Fluorescent probes (fluoroprobes) such as thioflavin T 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 to screen the Aurora collection of 300+ fluoroprobes against multiple synthetic fibril polymorphs, including those formed from tau, α-synuclein and islet amyloid polypeptide. This screen—coupled with excitation-multiplexed bright-emission recording (EMBER) imaging and orthogonal secondary assays—revealed pan-fibril-binding chemotypes, as well as fluoroprobes selective for fibril subsets. One fluoroprobe recognized tau pathology in ex vivo brain slices from Alzheimer’s disease and rodent models. We propose that these scaffolds represent entry points for developing fibril-selective ligands.
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Item Type: | Article |
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Copyright, Publisher and Additional Information: | © The Author(s) 2025. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/ licenses/by/4.0/. |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 27 Aug 2025 15:04 |
Last Modified: | 27 Aug 2025 15:04 |
Published Version: | https://www.nature.com/articles/s41557-025-01889-7 |
Status: | Published online |
Publisher: | Springer Nature |
Identification Number: | 10.1038/s41557-025-01889-7 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:230701 |
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