Imaging Aβ(1-42) fibril elongation reveals strongly polarised growth and growth incompetent states.
Publication Date
2017-10Journal Title
Physical chemistry chemical physics : PCCP
ISSN
1463-9076
Publisher
RSC
Volume
19
Issue
41
Pages
27987-27996
Language
eng
Type
Article
This Version
AM
Physical Medium
Print
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Young, L. J., Kaminski, G., & Kaminski, C. (2017). Imaging Aβ(1-42) fibril elongation reveals strongly polarised growth and growth incompetent states.. Physical chemistry chemical physics : PCCP, 19 (41), 27987-27996. https://doi.org/10.1039/c7cp03412a
Abstract
The major hallmark of Alzheimer’s disease is the deposition of plaques of amyloid fibrils formed from amyloid-beta (Ab) peptides. Kinetic studies have contributed significantly towards a mechanistic understanding of amyloid fibril self-assembly, however dynamic features of the aggregation process
cannot be captured using ensemble methods. Here we present an assay for imaging Ab42 aggregation dynamics at the single fibril level, allowing for the quantitative extraction of concentration and temperature dependent kinetic parameters. From direct observation of elongation using TIRF and superresolution optical microscopy, we find that Ab42 fibril growth is strongly polarized, with fast and slow growing ends arising from different elongation rates, but also from a growth incompetent state, which dominates the process at the slow growing end. Our findings reveal the surprising complexity of the Ab42 fibril elongation reaction at the microscopic level.
Sponsorship
MRC (MR/K02292X/1)
EPSRC (EP/L015889/1)
EPSRC (1108165)
Wellcome Trust (203249/Z/16/Z)
EPSRC (EP/H018301/1)
MRC (MR/K015850/1)
MRC (G0902243)
Wellcome Trust (089703/Z/09/Z)
EPSRC (EP/G037221/1)
BBSRC (BB/H023917/1)
Identifiers
External DOI: https://doi.org/10.1039/c7cp03412a
This record's URL: https://www.repository.cam.ac.uk/handle/1810/275181
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