Ultrastructural evidence for self-replication of Alzheimer-associated Aβ42 amyloid along the sides of fibrils

Mattias Törnquist*, Risto Cukalevski, Ulrich Weininger, Georg Meisl, Tuomas P.J. Knowles, Thom Leiding, Anders Malmendal, Mikael Akke, Sara Linse*

*Corresponding author

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Abstract

The nucleation of Alzheimer-associated Aβ peptide monomers can
be catalyzed by preexisting Aβ fibrils. This leads to autocatalytic
amplification of aggregate mass and underlies self-replication and
generation of toxic oligomers associated with several neurodegenerative
diseases. However, the nature of the interactions between
the monomeric species and the fibrils during this key
process, and indeed the ultrastructural localization of the interaction
sites have remained elusive. Here we used NMR and optical
spectroscopy to identify conditions that enable the capture of transient
species during the aggregation and secondary nucleation of the
Aβ42 peptide. Cryo-electron microscopy (cryo-EM) images show that
new aggregates protrude from the entire length of the progenitor
fibril. These protrusions are morphologically distinct from the wellordered
fibrils dominating at the end of the aggregation process. The
data provide direct evidence that self-replication through secondary
nucleation occurs along the sides of fibrils, which become heavily
decorated under the current solution conditions (14 μM Aβ42,
20 mM sodium phosphate, 200 μM EDTA, pH 6.8).

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