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

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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 P.J.; Leiding, Thom; Linse, Sara.

In: Communications Biology, Vol. 2, No. 1, 365, 2019.

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T1 - Autocatalytic amplification of Alzheimer-associated Aβ42 peptide aggregation in human cerebrospinal fluid

AU - Frankel, Rebecca

AU - Törnquist, Mattias

AU - Meisl, Georg

AU - Hansson, Oskar

AU - Andreasson, Ulf

AU - Zetterberg, Henrik

AU - Blennow, Kaj

AU - Frohm, Birgitta

AU - Cedervall, Tommy

AU - Knowles, Tuomas P.J.

AU - Leiding, Thom

AU - Linse, Sara

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

U2 - 10.1038/s42003-019-0612-2

DO - 10.1038/s42003-019-0612-2

M3 - Article

VL - 2

JO - Communications Biology

JF - Communications Biology

SN - 2399-3642

IS - 1

M1 - 365

ER -