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Autocatalytic amplification of Alzheimer-associated A beta 42 peptide aggregation in human cerebrospinal fluid

Journal article
Authors R. Frankel
M. Tornquist
G. Meisl
O. Hansson
U. Andreasson
Henrik Zetterberg
Kaj Blennow
B. Frohm
T. Cedervall
T. P. J. Knowles
T. Leiding
S. Linse
Published in Communications Biology
Volume 2
Publication year 2019
Published at Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry
Language en
Links dx.doi.org/10.1038/s42003-019-0612-...
Keywords atomic-resolution structure, secondary nucleation, protein aggregation, fibril formation, app gene, disease, mutation, precursor, purification, modulation
Subject categories Neurosciences

Abstract

Alzheimer's disease is linked to amyloid beta (A beta) peptide aggregation in the brain, and a detailed understanding of the molecular mechanism of A beta 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 A beta 42 in human CSF through kinetic experiments at several A beta 42 monomer concentrations (0.8-10 mu M). 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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