Abstract
Oligomers which form during amyloid fibril assembly are considered to be key contributors towards amyloid disease. However, understanding how such intermediates form, their structure, and mechanisms of toxicity presents significant challenges due to their transient and heterogeneous nature. Here, we discuss two different strategies for addressing these challenges: use of (1) methods capable of detecting lowly-populated species within complex mixtures, such as NMR, single particle methods (including fluorescence and force spectroscopy), and mass spectrometry; and (2) chemical and biological tools to bias the amyloid energy landscape towards specific oligomeric states. While the former methods are well suited to following the kinetics of amyloid assembly and obtaining low-resolution structural information, the latter are capable of producing oligomer samples for high-resolution structural studies and inferring structure-toxicity relationships. Together, these different approaches should enable a clearer picture to be gained of the nature and role of oligomeric intermediates in amyloid formation and disease.
Original language | English |
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Article number | 106505 |
Number of pages | 14 |
Journal | Biophysical Chemistry |
Volume | 268 |
Early online date | 10 Nov 2020 |
DOIs | |
Publication status | Published - Jan 2021 |
Bibliographical note
Funding Information:We thank members of our laboratories for helpful discussions. This work was supported by The Wellcome Trust (109154/Z/15/Z and 204963), the EPSRC (EP/N035267/1, EP/N013573/1) and the ERC (322408). A.J.W. holds a Royal Society Leverhulme Trust Senior Fellowship (SRF/R1/191087). EEC and TKK wrote the first draft. All authors curated information, reviewed, and edited the manuscript.
Publisher Copyright:
© 2020
Keywords
- Amyloid disease
- Chemical tool
- NMR
- Oligomer stabilization
- Single particle
- Transient intermediate
ASJC Scopus subject areas
- Biophysics
- Biochemistry
- Organic Chemistry