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Analysis of the length distribution of amyloid fibrils by centrifugal sedimentation

Arosio, Paolo; Cedervall, Tommy LU ; Knowles, Tuomas P J and Linse, Sara LU (2016) In Analytical Biochemistry 504. p.7-13
Abstract

The aggregation of normally soluble peptides and proteins into amyloid fibrils is a process associated with a wide range of pathological conditions, including Alzheimer's and Parkinson's diseases. It has become apparent that aggregates of different sizes possess markedly different biological effects, with aggregates of lower relative molecular weight being associated with stronger neurotoxicity. Yet, although many approaches exist to measure the total mass concentration of aggregates, the ability to probe the length distribution of growing aggregates in solution has remained more elusive. In this work, we applied a differential centrifugation technique to measure the sedimentation coefficients of amyloid fibrils produced during the... (More)

The aggregation of normally soluble peptides and proteins into amyloid fibrils is a process associated with a wide range of pathological conditions, including Alzheimer's and Parkinson's diseases. It has become apparent that aggregates of different sizes possess markedly different biological effects, with aggregates of lower relative molecular weight being associated with stronger neurotoxicity. Yet, although many approaches exist to measure the total mass concentration of aggregates, the ability to probe the length distribution of growing aggregates in solution has remained more elusive. In this work, we applied a differential centrifugation technique to measure the sedimentation coefficients of amyloid fibrils produced during the aggregation process of the amyloid β (M1-42) peptide (Aβ42). The centrifugal method has the advantage of providing structural information on the fibril distribution directly in solution and affording a short analysis time with respect to alternative imaging and analytical centrifugation approaches. We show that under quiescent conditions interactions between Aβ42 fibrils lead to lateral association and to the formation of entangled clusters. By contrast, aggregation under shaking generates a population of filaments characterized by shorter lengths. The results, which have been validated by cryogenic transmission electron microscopy (cryo-TEM) analysis, highlight the important role that fibril-fibril assembly can play in the deposition of aggregation-prone peptides.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Amyloid, Aβ peptide, Differential centrifugation, Length distribution, Polydispersity, Size distribution
in
Analytical Biochemistry
volume
504
pages
7 pages
publisher
Elsevier
external identifiers
  • Scopus:84964692173
  • WOS:000377055000003
ISSN
0003-2697
DOI
10.1016/j.ab.2016.03.015
language
English
LU publication?
yes
id
b5d5674e-f040-41a4-ab3d-1448839bf505
date added to LUP
2016-05-19 13:35:27
date last changed
2017-01-01 08:26:29
@article{b5d5674e-f040-41a4-ab3d-1448839bf505,
  abstract     = {<p>The aggregation of normally soluble peptides and proteins into amyloid fibrils is a process associated with a wide range of pathological conditions, including Alzheimer's and Parkinson's diseases. It has become apparent that aggregates of different sizes possess markedly different biological effects, with aggregates of lower relative molecular weight being associated with stronger neurotoxicity. Yet, although many approaches exist to measure the total mass concentration of aggregates, the ability to probe the length distribution of growing aggregates in solution has remained more elusive. In this work, we applied a differential centrifugation technique to measure the sedimentation coefficients of amyloid fibrils produced during the aggregation process of the amyloid β (M1-42) peptide (Aβ42). The centrifugal method has the advantage of providing structural information on the fibril distribution directly in solution and affording a short analysis time with respect to alternative imaging and analytical centrifugation approaches. We show that under quiescent conditions interactions between Aβ42 fibrils lead to lateral association and to the formation of entangled clusters. By contrast, aggregation under shaking generates a population of filaments characterized by shorter lengths. The results, which have been validated by cryogenic transmission electron microscopy (cryo-TEM) analysis, highlight the important role that fibril-fibril assembly can play in the deposition of aggregation-prone peptides.</p>},
  author       = {Arosio, Paolo and Cedervall, Tommy and Knowles, Tuomas P J and Linse, Sara},
  issn         = {0003-2697},
  keyword      = {Amyloid,Aβ peptide,Differential centrifugation,Length distribution,Polydispersity,Size distribution},
  language     = {eng},
  month        = {07},
  pages        = {7--13},
  publisher    = {Elsevier},
  series       = {Analytical Biochemistry},
  title        = {Analysis of the length distribution of amyloid fibrils by centrifugal sedimentation},
  url          = {http://dx.doi.org/10.1016/j.ab.2016.03.015},
  volume       = {504},
  year         = {2016},
}