Advanced

The role of fibril structure and surface hydrophobicity in secondary nucleation of amyloid fibrils

Thacker, Dev LU ; Sanagavarapu, Kalyani LU ; Frohm, Birgitta LU ; Meisl, Georg ; Knowles, Tuomas P.J. and Linse, Sara LU (2020) In Proceedings of the National Academy of Sciences of the United States of America 117(41). p.25272-25283
Abstract

Crystals, nanoparticles, and fibrils catalyze the generation of new aggregates on their surface from the same type of monomeric building blocks as the parent assemblies. This secondary nucleation process can be many orders of magnitude faster than primary nucleation. In the case of amyloid fibrils associated with Alzheimer's disease, this process leads to the multiplication and propagation of aggregates, whereby short-lived oligomeric intermediates cause neurotoxicity. Understanding the catalytic activity is a fundamental goal in elucidating the molecular mechanisms of Alzheimer's and associated diseases. Here we explore the role of fibril structure and hydrophobicity by asking whether the V18, A21, V40, and A42 side chains which are... (More)

Crystals, nanoparticles, and fibrils catalyze the generation of new aggregates on their surface from the same type of monomeric building blocks as the parent assemblies. This secondary nucleation process can be many orders of magnitude faster than primary nucleation. In the case of amyloid fibrils associated with Alzheimer's disease, this process leads to the multiplication and propagation of aggregates, whereby short-lived oligomeric intermediates cause neurotoxicity. Understanding the catalytic activity is a fundamental goal in elucidating the molecular mechanisms of Alzheimer's and associated diseases. Here we explore the role of fibril structure and hydrophobicity by asking whether the V18, A21, V40, and A42 side chains which are exposed on the Aβ42 fibril surface as continuous hydrophobic patches play a role in secondary nucleation. Single, double, and quadruple serine substitutions were made. Kinetic analyses of aggregation data at multiple monomer concentrations reveal that all seven mutants retain the dominance of secondary nucleation as the main mechanism of fibril proliferation. This finding highlights the generality of secondary nucleation and its independence of the detailed molecular structure. Cryo-electron micrographs reveal that the V18S substitution causes fibrils to adopt a distinct morphology with longer twist distance than variants lacking this substitution. Self- and cross-seeding data show that surface catalysis is only efficient between peptides of identical morphology, indicating a templating role of secondary nucleation with structural conversion at the fibril surface. Our findings thus provide clear evidence that the propagation of amyloid fibril strains is possible even in systems dominated by secondary nucleation rather than fragmentation.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Amyloid, Secondary nucleation, Strain propagation, Surface catalysis
in
Proceedings of the National Academy of Sciences of the United States of America
volume
117
issue
41
pages
12 pages
publisher
National Acad Sciences
external identifiers
  • pmid:33004626
  • scopus:85092906143
ISSN
0027-8424
DOI
10.1073/pnas.2002956117
language
English
LU publication?
yes
id
b2f2cd10-72fd-49cf-8cc2-8f261b244ebd
date added to LUP
2020-11-06 10:18:34
date last changed
2021-04-06 03:51:09
@article{b2f2cd10-72fd-49cf-8cc2-8f261b244ebd,
  abstract     = {<p>Crystals, nanoparticles, and fibrils catalyze the generation of new aggregates on their surface from the same type of monomeric building blocks as the parent assemblies. This secondary nucleation process can be many orders of magnitude faster than primary nucleation. In the case of amyloid fibrils associated with Alzheimer's disease, this process leads to the multiplication and propagation of aggregates, whereby short-lived oligomeric intermediates cause neurotoxicity. Understanding the catalytic activity is a fundamental goal in elucidating the molecular mechanisms of Alzheimer's and associated diseases. Here we explore the role of fibril structure and hydrophobicity by asking whether the V18, A21, V40, and A42 side chains which are exposed on the Aβ42 fibril surface as continuous hydrophobic patches play a role in secondary nucleation. Single, double, and quadruple serine substitutions were made. Kinetic analyses of aggregation data at multiple monomer concentrations reveal that all seven mutants retain the dominance of secondary nucleation as the main mechanism of fibril proliferation. This finding highlights the generality of secondary nucleation and its independence of the detailed molecular structure. Cryo-electron micrographs reveal that the V18S substitution causes fibrils to adopt a distinct morphology with longer twist distance than variants lacking this substitution. Self- and cross-seeding data show that surface catalysis is only efficient between peptides of identical morphology, indicating a templating role of secondary nucleation with structural conversion at the fibril surface. Our findings thus provide clear evidence that the propagation of amyloid fibril strains is possible even in systems dominated by secondary nucleation rather than fragmentation.</p>},
  author       = {Thacker, Dev and Sanagavarapu, Kalyani and Frohm, Birgitta and Meisl, Georg and Knowles, Tuomas P.J. and Linse, Sara},
  issn         = {0027-8424},
  language     = {eng},
  number       = {41},
  pages        = {25272--25283},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences of the United States of America},
  title        = {The role of fibril structure and surface hydrophobicity in secondary nucleation of amyloid fibrils},
  url          = {http://dx.doi.org/10.1073/pnas.2002956117},
  doi          = {10.1073/pnas.2002956117},
  volume       = {117},
  year         = {2020},
}