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A closer look at amyloid ligands, and what they tell us about protein aggregates.

Published version
Peer-reviewed

Repository DOI


Change log

Authors

Chisholm, Timothy S  ORCID logo  https://orcid.org/0000-0002-8693-3797
Hunter, Christopher A  ORCID logo  https://orcid.org/0000-0002-5182-1859

Abstract

The accumulation of amyloid fibrils is characteristic of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease. Detecting these fibrils with fluorescent or radiolabelled ligands is one strategy for diagnosing and better understanding these diseases. A vast number of amyloid-binding ligands have been reported in the literature as a result. To obtain a better understanding of how amyloid ligands bind, we have compiled a database of 3457 experimental dissociation constants for 2076 unique amyloid-binding ligands. These ligands target Aβ, tau, or αSyn fibrils, as well as relevant biological samples including AD brain homogenates. From this database significant variation in the reported dissociation constants of ligands was found, possibly due to differences in the morphology of the fibrils being studied. Ligands were also found to bind to Aβ(1-40) and Aβ(1-42) fibrils with similar affinities, whereas a greater difference was found for binding to Aβ and tau or αSyn fibrils. Next, the binding of ligands to fibrils was shown to be largely limited by the hydrophobic effect. Some Aβ ligands do not fit into this hydrophobicity-limited model, suggesting that polar interactions can play an important role when binding to this target. Finally several binding site models were outlined for amyloid fibrils that describe what ligands target what binding sites. These models provide a foundation for interpreting and designing site-specific binding assays.

Description

Acknowledgements: We thank the Cambridge Trust Prince of Wales Scholarship for funding T. S. C.

Keywords

Humans, Amyloid beta-Peptides, Protein Aggregates, Amyloid, Alzheimer Disease, Amyloidogenic Proteins

Journal Title

Chem Soc Rev

Conference Name

Journal ISSN

0306-0012
1460-4744

Volume Title

Publisher

Royal Society of Chemistry (RSC)
Sponsorship
Cambridge Trust (Prince of Wales Scholarship)
Cambridge Trust Prince of Wales Scholarship