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ThX-a next-generation probe for the early detection of amyloid aggregates

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Author(s)

Lisa Maria Needham, Judith Weber, Juan A. Varela, James W.B. Fyfe, Dung T. Do, Catherine K. Xu, Luke Tutton, Rachel Cliffe, Benjamin Keenlyside, David Klenerman, Christopher M. Dobson, Christopher A. Hunter, Karin H. Müller, Kevin O'Holleran, Sarah E. Bohndiek, Thomas N. Snaddon, Steven F. Lee

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Abstract

Neurodegenerative diseases such as Alzheimer's and Parkinson's are associated with protein misfolding and aggregation. Recent studies suggest that the small, rare and heterogeneous oligomeric species, formed early on in the aggregation process, may be a source of cytotoxicity. Thioflavin T (ThT) is currently the gold-standard fluorescent probe for the study of amyloid proteins and aggregation processes. However, the poor photophysical and binding properties of ThT impairs the study of oligomers. To overcome this challenge, we have designed Thioflavin X, (ThX), a next-generation fluorescent probe which displays superior properties; including a 5-fold increase in brightness and 7-fold increase in binding affinity to amyloidogenic proteins. As an extrinsic dye, this can be used to study unique structural amyloid features both in bulk and on a single-aggregate level. Furthermore, ThX can be used as a super-resolution imaging probe in single-molecule localisation microscopy. Finally, the improved optical properties (extinction coefficient, quantum yield and brightness) of ThX can be used to monitor structural differences in oligomeric species, not observed via traditional ThT imaging.

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Original languageEnglish
Pages (from-to)4578-4583
Number of pages6
JournalChemical Science
Volume11
Issue number18
Early online date21 Feb 2020
DOIs
Publication statusPublished - 14 May 2020

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