Dynamics of oligomer populations formed during the aggregation of Alzheimer's Aβ42 peptide.
- Michaels TCT Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge, UK.
- Šarić A Department of Physics and Astronomy, Institute for the Physics of Living Systems, University College London, London, UK.
- Curk S Department of Physics and Astronomy, Institute for the Physics of Living Systems, University College London, London, UK.
- Bernfur K Department of Chemistry, Division for Biochemistry and Structural Biology, Lund University, Lund, Sweden.
- Arosio P Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland.
- Meisl G Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge, UK.
- Dear AJ Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge, UK.
- Cohen SIA Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge, UK.
- Dobson CM Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge, UK.
- Vendruscolo M Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge, UK. mv245@cam.ac.uk.
- Linse S Department of Chemistry, Division for Biochemistry and Structural Biology, Lund University, Lund, Sweden. Sara.Linse@biochemistry.lu.se.
- Knowles TPJ Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge, UK. tpjk2@cam.ac.uk.
- 2020-04-15
Published in:
- Nature chemistry. - 2020
English
Oligomeric species populated during the aggregation of the Aβ42 peptide have been identified as potent cytotoxins linked to Alzheimer's disease, but the fundamental molecular pathways that control their dynamics have yet to be elucidated. By developing a general approach that combines theory, experiment and simulation, we reveal, in molecular detail, the mechanisms of Aβ42 oligomer dynamics during amyloid fibril formation. Even though all mature amyloid fibrils must originate as oligomers, we found that most Aβ42 oligomers dissociate into their monomeric precursors without forming new fibrils. Only a minority of oligomers converts into fibrillar structures. Moreover, the heterogeneous ensemble of oligomeric species interconverts on timescales comparable to those of aggregation. Our results identify fundamentally new steps that could be targeted by therapeutic interventions designed to combat protein misfolding diseases.
- Language
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- English
- Open access status
- green
- Identifiers
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- DOI 10.1038/s41557-020-0452-1
- PMID 32284577
- Persistent URL
- https://sonar.ch/global/documents/175378
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