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Quantitative analysis of intrinsic and extrinsic factors in the aggregation mechanism of Alzheimer-associated Aβ-peptide.

Meisl, Georg; Yang, Xiaoting LU ; Frohm, Birgitta LU ; Knowles, Tuomas P J and Linse, Sara LU (2016) In Scientific Reports 6.
Abstract
Disease related mutations and environmental factors are key determinants of the aggregation mechanism of the amyloid-β peptide implicated in Alzheimer's disease. Here we present an approach to investigate these factors through acquisition of highly reproducible data and global kinetic analysis to determine the mechanistic influence of intrinsic and extrinsic factors on the Aβ aggregation network. This allows us to translate the shift in macroscopic aggregation behaviour into effects on the individual underlying microscopic steps. We apply this work-flow to the disease-associated Aβ42-A2V variant, and to a variation in pH as examples of an intrinsic and an extrinsic perturbation. In both cases, our data reveal a shift towards a mechanism in... (More)
Disease related mutations and environmental factors are key determinants of the aggregation mechanism of the amyloid-β peptide implicated in Alzheimer's disease. Here we present an approach to investigate these factors through acquisition of highly reproducible data and global kinetic analysis to determine the mechanistic influence of intrinsic and extrinsic factors on the Aβ aggregation network. This allows us to translate the shift in macroscopic aggregation behaviour into effects on the individual underlying microscopic steps. We apply this work-flow to the disease-associated Aβ42-A2V variant, and to a variation in pH as examples of an intrinsic and an extrinsic perturbation. In both cases, our data reveal a shift towards a mechanism in which a larger fraction of the reactive flux goes via a pathway that generates potentially toxic oligomeric species in a fibril-catalyzed reaction. This is in agreement with the finding that Aβ42-A2V leads to early-onset Alzheimer's disease and enhances neurotoxicity. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Scientific Reports
volume
6
publisher
Nature Publishing Group
external identifiers
  • pmid:26758487
  • wos:000368097900001
  • scopus:84954480111
ISSN
2045-2322
DOI
10.1038/srep18728
language
English
LU publication?
yes
id
793d4b60-cd0c-4359-ac19-7f2bdb9186fe (old id 8592243)
date added to LUP
2016-02-10 14:05:35
date last changed
2017-11-12 03:36:47
@article{793d4b60-cd0c-4359-ac19-7f2bdb9186fe,
  abstract     = {Disease related mutations and environmental factors are key determinants of the aggregation mechanism of the amyloid-β peptide implicated in Alzheimer's disease. Here we present an approach to investigate these factors through acquisition of highly reproducible data and global kinetic analysis to determine the mechanistic influence of intrinsic and extrinsic factors on the Aβ aggregation network. This allows us to translate the shift in macroscopic aggregation behaviour into effects on the individual underlying microscopic steps. We apply this work-flow to the disease-associated Aβ42-A2V variant, and to a variation in pH as examples of an intrinsic and an extrinsic perturbation. In both cases, our data reveal a shift towards a mechanism in which a larger fraction of the reactive flux goes via a pathway that generates potentially toxic oligomeric species in a fibril-catalyzed reaction. This is in agreement with the finding that Aβ42-A2V leads to early-onset Alzheimer's disease and enhances neurotoxicity.},
  articleno    = {8728},
  author       = {Meisl, Georg and Yang, Xiaoting and Frohm, Birgitta and Knowles, Tuomas P J and Linse, Sara},
  issn         = {2045-2322},
  language     = {eng},
  publisher    = {Nature Publishing Group},
  series       = {Scientific Reports},
  title        = {Quantitative analysis of intrinsic and extrinsic factors in the aggregation mechanism of Alzheimer-associated Aβ-peptide.},
  url          = {http://dx.doi.org/10.1038/srep18728},
  volume       = {6},
  year         = {2016},
}