ThX – a next-generation probe for the early detection of amyloid aggregates |
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| Authors: | 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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| Institution: | Department of Chemistry, University of Cambridge, Cambridge CB2 1EW UK.; Department of Physics, University of Cambridge, Cambridge CB3 0HE UK ; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE UK ; Biomedical Sciences Research Complex, School of Biology, University of St Andrews, St Andrews UK ; Department of Chemistry, Indiana University, Bloomington 47405 USA.; Cambridge Advanced Imaging Centre, University of Cambridge, Cambridge CB2 3DY UK |
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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.Introducing ThX, a next-generation ThT derivative that allows for the early detection of amyloid aggregates at the bulk and single-aggregate levels. |
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