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

Michaels, Thomas C.T. ; Šarić, Andela ; Curk, Samo ; Bernfur, Katja LU ; Arosio, Paolo ; Meisl, Georg ; Dear, Alexander J. ; Cohen, Samuel I.A. ; Dobson, Christopher M. and Vendruscolo, Michele , et al. (2020) In Nature Chemistry 12(5). p.445-451
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... (More)

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. [Figure not available: see fulltext.].

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Contribution to journal
publication status
published
subject
in
Nature Chemistry
volume
12
issue
5
pages
7 pages
publisher
Nature Publishing Group
external identifiers
  • pmid:32284577
  • scopus:85084027236
ISSN
1755-4330
DOI
10.1038/s41557-020-0452-1
language
English
LU publication?
yes
id
560bde5b-1b5e-491a-b2af-88746c1ca412
date added to LUP
2020-05-19 08:48:05
date last changed
2021-02-21 05:40:10
@article{560bde5b-1b5e-491a-b2af-88746c1ca412,
  abstract     = {<p>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. [Figure not available: see fulltext.].</p>},
  author       = {Michaels, Thomas C.T. and Šarić, Andela and Curk, Samo and Bernfur, Katja and Arosio, Paolo and Meisl, Georg and Dear, Alexander J. and Cohen, Samuel I.A. and Dobson, Christopher M. and Vendruscolo, Michele and Linse, Sara and Knowles, Tuomas P.J.},
  issn         = {1755-4330},
  language     = {eng},
  number       = {5},
  pages        = {445--451},
  publisher    = {Nature Publishing Group},
  series       = {Nature Chemistry},
  title        = {Dynamics of oligomer populations formed during the aggregation of Alzheimer’s Aβ42 peptide},
  url          = {http://dx.doi.org/10.1038/s41557-020-0452-1},
  doi          = {10.1038/s41557-020-0452-1},
  volume       = {12},
  year         = {2020},
}