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Autocatalytic amplification of Alzheimer-associated Aβ42 peptide aggregation in human cerebrospinal fluid

Frankel, Rebecca LU ; Törnquist, Mattias LU ; Meisl, Georg ; Hansson, Oskar LU ; Andreasson, Ulf ; Zetterberg, Henrik LU ; Blennow, Kaj LU ; Frohm, Birgitta LU ; Cedervall, Tommy LU and Knowles, Tuomas P.J. , et al. (2019) In Communications Biology 2(1).
Abstract

Alzheimer’s disease is linked to amyloid β (Aβ) peptide aggregation in the brain, and a detailed understanding of the molecular mechanism of Aβ aggregation may lead to improved diagnostics and therapeutics. While previous studies have been performed in pure buffer, we approach the mechanism in vivo using cerebrospinal fluid (CSF). We investigated the aggregation mechanism of Aβ42 in human CSF through kinetic experiments at several Aβ42 monomer concentrations (0.8–10 µM). The data were subjected to global kinetic analysis and found consistent with an aggregation mechanism involving secondary nucleation of monomers on the fibril surface. A mechanism only including primary nucleation was ruled out. We find that the aggregation process is... (More)

Alzheimer’s disease is linked to amyloid β (Aβ) peptide aggregation in the brain, and a detailed understanding of the molecular mechanism of Aβ aggregation may lead to improved diagnostics and therapeutics. While previous studies have been performed in pure buffer, we approach the mechanism in vivo using cerebrospinal fluid (CSF). We investigated the aggregation mechanism of Aβ42 in human CSF through kinetic experiments at several Aβ42 monomer concentrations (0.8–10 µM). The data were subjected to global kinetic analysis and found consistent with an aggregation mechanism involving secondary nucleation of monomers on the fibril surface. A mechanism only including primary nucleation was ruled out. We find that the aggregation process is composed of the same microscopic steps in CSF as in pure buffer, but the rate constant of secondary nucleation is decreased. Most importantly, the autocatalytic amplification of aggregate number through catalysis on the fibril surface is prevalent also in CSF.

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publication status
published
subject
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Communications Biology
volume
2
issue
1
article number
365
publisher
Nature Research
external identifiers
  • scopus:85073564439
ISSN
2399-3642
DOI
10.1038/s42003-019-0612-2
language
English
LU publication?
yes
id
01c98f9e-3f0f-4304-b30b-0e3128910cb5
date added to LUP
2019-10-25 11:17:19
date last changed
2020-03-24 07:05:12
@article{01c98f9e-3f0f-4304-b30b-0e3128910cb5,
  abstract     = {<p>Alzheimer’s disease is linked to amyloid β (Aβ) peptide aggregation in the brain, and a detailed understanding of the molecular mechanism of Aβ aggregation may lead to improved diagnostics and therapeutics. While previous studies have been performed in pure buffer, we approach the mechanism in vivo using cerebrospinal fluid (CSF). We investigated the aggregation mechanism of Aβ42 in human CSF through kinetic experiments at several Aβ42 monomer concentrations (0.8–10 µM). The data were subjected to global kinetic analysis and found consistent with an aggregation mechanism involving secondary nucleation of monomers on the fibril surface. A mechanism only including primary nucleation was ruled out. We find that the aggregation process is composed of the same microscopic steps in CSF as in pure buffer, but the rate constant of secondary nucleation is decreased. Most importantly, the autocatalytic amplification of aggregate number through catalysis on the fibril surface is prevalent also in CSF.</p>},
  author       = {Frankel, Rebecca and Törnquist, Mattias and Meisl, Georg and Hansson, Oskar and Andreasson, Ulf and Zetterberg, Henrik and Blennow, Kaj and Frohm, Birgitta and Cedervall, Tommy and Knowles, Tuomas P.J. and Leiding, Thom and Linse, Sara},
  issn         = {2399-3642},
  language     = {eng},
  number       = {1},
  publisher    = {Nature Research},
  series       = {Communications Biology},
  title        = {Autocatalytic amplification of Alzheimer-associated Aβ42 peptide aggregation in human cerebrospinal fluid},
  url          = {http://dx.doi.org/10.1038/s42003-019-0612-2},
  doi          = {10.1038/s42003-019-0612-2},
  volume       = {2},
  year         = {2019},
}