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

  • Frankel, Rebecca
  • Törnquist, Mattias
  • Meisl, Georg
  • Hansson, Oskar
  • Andreasson, Ulf
  • Zetterberg, Henrik
  • Blennow, Kaj
  • Frohm, Birgitta
  • Cedervall, Tommy
  • Knowles, Tuomas
  • Leiding, Thom
  • Linse, Sara
Publication Date
Dec 07, 2019
Apollo - University of Cambridge Repository
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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. / This work was funded by the European Research Council (S.L.), The Swedish Research Council (S.L.), The Knut and Alice Wallenberg Foundation (S.L.) and Alzheimerfonden (S.L., O.H., H.Z., K.B.). H.Z. is a Wallenberg Academy Fellow.

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