High-throughput discovery of fluoroprobes that recognize amyloid fibril polymorphs
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
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
