Ultrastructural evidence for self-replication of alzheimer-associated Aβ42 amyloid along the sides of fibrils
Tornquist, Mattias LU ; Cukalevski, Risto LU ; Weininger, Ulrich LU ; Meisl, Georg ; Knowles, Tuomas P.J. ; Leiding, Thom LU ; Malmendal, Anders LU ; Akke, Mikael LU
and Linse, Sara
LU
(2020)
In Proceedings of the National Academy of Sciences of the United States of America
117(21).
p.11265-11273
- 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... (More)
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).
(Less)
- author
- Tornquist, Mattias
LU
; Cukalevski, Risto
LU
; Weininger, Ulrich
LU
; Meisl, Georg
; Knowles, Tuomas P.J.
; Leiding, Thom
LU
; Malmendal, Anders
LU
; Akke, Mikael
LU
and Linse, Sara
LU
- organization
- publishing date
- 2020-05-26
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Aggregation mechanism, Amyloidosis, Fibril formation, Neurodegeneration, Self-assembly
- in
- Proceedings of the National Academy of Sciences of the United States of America
- volume
- 117
- issue
- 21
- pages
- 9 pages
- publisher
- National Academy of Sciences
- external identifiers
-
- pmid:32439711
- scopus:85085467631
- ISSN
- 0027-8424
- DOI
- 10.1073/pnas.1918481117
- language
- English
- LU publication?
- yes
- id
- aa1968c9-5827-4968-b104-ea108c3c33fc
- date added to LUP
- 2020-06-16 13:21:49
- date last changed
- 2024-11-14 08:29:00
@article{aa1968c9-5827-4968-b104-ea108c3c33fc,
abstract = {{<p>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).</p>}},
author = {{Tornquist, Mattias and Cukalevski, Risto and Weininger, Ulrich and Meisl, Georg and Knowles, Tuomas P.J. and Leiding, Thom and Malmendal, Anders and Akke, Mikael and Linse, Sara}},
issn = {{0027-8424}},
keywords = {{Aggregation mechanism; Amyloidosis; Fibril formation; Neurodegeneration; Self-assembly}},
language = {{eng}},
month = {{05}},
number = {{21}},
pages = {{11265--11273}},
publisher = {{National Academy of Sciences}},
series = {{Proceedings of the National Academy of Sciences of the United States of America}},
title = {{Ultrastructural evidence for self-replication of alzheimer-associated Aβ42 amyloid along the sides of fibrils}},
url = {{http://dx.doi.org/10.1073/pnas.1918481117}},
doi = {{10.1073/pnas.1918481117}},
volume = {{117}},
year = {{2020}},
}