High-Throughput Discovery of Fluoroprobes That Recognize Amyloid Fibril Polymorphs

Authors

• Emma C. Carroll, San Jose State UniversityFollow
• Hyunjun Yang, University of California, San Francisco
• Wyatt C. Powell, University of California, San Francisco
• Annemarie F. Charvat, University of California, San Francisco
• Abby Oehler, University of California, San Francisco
• Julia G. Jones, University of California, San Francisco
• Kelly M. Montgomery, University of California, San Francisco
• Anthony Yung, University of California, San Francisco
• Zoe Millbern, NC State University
• Alexander I.P. Taylor, University of Leeds
• Martin Wilkinson, University of Leeds
• Neil A. Ranson, University of Leeds
• Sheena E. Radford, University of Leeds
• Nelson R. Vinueza, NC State University
• William F. DeGrado, University of California, San Francisco
• Daniel A. Mordes, University of California, San Francisco
• Carlo Condello, University of California, San Francisco
• Jason E. Gestwicki, University of California, San Francisco

Publication Date

1-1-2025

Document Type

Article

Publication Title

Nature Chemistry

DOI

10.1038/s41557-025-01889-7

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. (Figure presented.)

Funding Number

RSRP\R1\211057

Funding Sponsor

Tau Consortium

Comments

Correction to: Nature Chemistry https://doi.org/10.1038/s41557-025-01889-7, published online 14 August 2025.

In the version of this article initially published, in the Fig. 5a coumarins panel, there were errors where the labels now reading left-to-right as “L016 (Coumarin 481)” and “L017 (Coumarin 485)” appeared originally as “L017 (Coumarin 485)” and “L016,” while in the polymethines panel, there were graphical errors in the structures shown for L063 and L095. The labels and structures are now amended in the HTML and PDF versions of the article.

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

Department

Chemistry

Recommended Citation

Emma C. Carroll, Hyunjun Yang, Wyatt C. Powell, Annemarie F. Charvat, Abby Oehler, Julia G. Jones, Kelly M. Montgomery, Anthony Yung, Zoe Millbern, Alexander I.P. Taylor, Martin Wilkinson, Neil A. Ranson, Sheena E. Radford, Nelson R. Vinueza, William F. DeGrado, Daniel A. Mordes, Carlo Condello, and Jason E. Gestwicki. "High-Throughput Discovery of Fluoroprobes That Recognize Amyloid Fibril Polymorphs" Nature Chemistry (2025). https://doi.org/10.1038/s41557-025-01889-7