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Dynamics of oligomer populations formed during the aggregation of Alzheimer's Aβ42 peptide

Michaels, TCT; Šarić, A; Curk, S; Bernfur, K; Arosio, P; Meisl, G; Dear, AJ; ... Knowles, TPJ; + view all (2020) Dynamics of oligomer populations formed during the aggregation of Alzheimer's Aβ42 peptide. Nature Chemistry , 12 pp. 445-451. 10.1038/s41557-020-0452-1. Green open access

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Abstract

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.

Type: Article
Title: Dynamics of oligomer populations formed during the aggregation of Alzheimer's Aβ42 peptide
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41557-020-0452-1
Publisher version: https://doi.org/10.1038/s41557-020-0452-1
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Biophysical chemistry, Kinetics, Protein aggregation, Supramolecular assembly
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Physics and Astronomy
URI: https://discovery.ucl.ac.uk/id/eprint/10101686
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