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Direct measurement of lipid membrane disruption connects kinetics and toxicity of Aβ42 aggregation

Flagmeier, Patrick ; De, Suman ; Michaels, Thomas C.T. ; Yang, Xiaoting LU ; Dear, Alexander J. ; Emanuelsson, Cecilia LU ; Vendruscolo, Michele ; Linse, Sara LU ; Klenerman, David and Knowles, Tuomas P.J. , et al. (2020) In Nature Structural and Molecular Biology 27(10). p.886-891
Abstract

The formation of amyloid deposits in human tissues is a defining feature of more than 50 medical disorders, including Alzheimer’s disease. Strong genetic and histological evidence links these conditions to the process of protein aggregation, yet it has remained challenging to identify a definitive connection between aggregation and pathogenicity. Using time-resolved fluorescence microscopy of individual synthetic vesicles, we show for the Aβ42 peptide implicated in Alzheimer’s disease that the disruption of lipid bilayers correlates linearly with the time course of the levels of transient oligomers generated through secondary nucleation. These findings indicate a specific role of oligomers generated through the catalytic action of... (More)

The formation of amyloid deposits in human tissues is a defining feature of more than 50 medical disorders, including Alzheimer’s disease. Strong genetic and histological evidence links these conditions to the process of protein aggregation, yet it has remained challenging to identify a definitive connection between aggregation and pathogenicity. Using time-resolved fluorescence microscopy of individual synthetic vesicles, we show for the Aβ42 peptide implicated in Alzheimer’s disease that the disruption of lipid bilayers correlates linearly with the time course of the levels of transient oligomers generated through secondary nucleation. These findings indicate a specific role of oligomers generated through the catalytic action of fibrillar species during the protein aggregation process in driving deleterious biological function and establish a direct causative connection between amyloid formation and its pathological effects.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Structural and Molecular Biology
volume
27
issue
10
pages
6 pages
publisher
Nature Publishing Group
external identifiers
  • pmid:32778821
  • scopus:85089256120
ISSN
1545-9993
DOI
10.1038/s41594-020-0471-z
language
English
LU publication?
yes
id
449d1dc4-cfd8-4fec-9dd5-4f73705033e8
date added to LUP
2020-08-20 08:45:42
date last changed
2021-02-17 05:04:30
@article{449d1dc4-cfd8-4fec-9dd5-4f73705033e8,
  abstract     = {<p>The formation of amyloid deposits in human tissues is a defining feature of more than 50 medical disorders, including Alzheimer’s disease. Strong genetic and histological evidence links these conditions to the process of protein aggregation, yet it has remained challenging to identify a definitive connection between aggregation and pathogenicity. Using time-resolved fluorescence microscopy of individual synthetic vesicles, we show for the Aβ42 peptide implicated in Alzheimer’s disease that the disruption of lipid bilayers correlates linearly with the time course of the levels of transient oligomers generated through secondary nucleation. These findings indicate a specific role of oligomers generated through the catalytic action of fibrillar species during the protein aggregation process in driving deleterious biological function and establish a direct causative connection between amyloid formation and its pathological effects.</p>},
  author       = {Flagmeier, Patrick and De, Suman and Michaels, Thomas C.T. and Yang, Xiaoting and Dear, Alexander J. and Emanuelsson, Cecilia and Vendruscolo, Michele and Linse, Sara and Klenerman, David and Knowles, Tuomas P.J. and Dobson, Christopher M.},
  issn         = {1545-9993},
  language     = {eng},
  number       = {10},
  pages        = {886--891},
  publisher    = {Nature Publishing Group},
  series       = {Nature Structural and Molecular Biology},
  title        = {Direct measurement of lipid membrane disruption connects kinetics and toxicity of Aβ42 aggregation},
  url          = {http://dx.doi.org/10.1038/s41594-020-0471-z},
  doi          = {10.1038/s41594-020-0471-z},
  volume       = {27},
  year         = {2020},
}