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Secondary nucleation and elongation occur at different sites on Alzheimer's amyloid-b aggregates

Scheidt, Tom; Łapińska, Urszula; Kumita, Janet R.; Whiten, Daniel R.; Klenerman, David; Wilson, Mark R.; Cohen, Samuel I.A.; Linse, Sara LU ; Vendruscolo, Michele and Dobson, Christopher M., et al. (2019) In Science Advances 5(4).
Abstract

The aggregates of the Ab peptide associated with Alzheimer's disease are able to both grow in size aswell as generate, through secondary nucleation, new small oligomeric species, that are major cytotoxins associated with neuronal death. Despite the importance of these amyloid fibril-dependent processes, their structural and molecular underpinnings have remained challenging to elucidate. Here, we consider two molecular chaperones: The Brichos domain, which suppresses specifically secondary nucleation processes, and clusterin which our results show is capable of inhibiting, specifically, the elongation of Ab fibrils at remarkably low substoichiometric ratios. Microfluidic diffusional sizing measurements demonstrate that this inhibition... (More)

The aggregates of the Ab peptide associated with Alzheimer's disease are able to both grow in size aswell as generate, through secondary nucleation, new small oligomeric species, that are major cytotoxins associated with neuronal death. Despite the importance of these amyloid fibril-dependent processes, their structural and molecular underpinnings have remained challenging to elucidate. Here, we consider two molecular chaperones: The Brichos domain, which suppresses specifically secondary nucleation processes, and clusterin which our results show is capable of inhibiting, specifically, the elongation of Ab fibrils at remarkably low substoichiometric ratios. Microfluidic diffusional sizing measurements demonstrate that this inhibition originates from interactions of clusterin with fibril ends with high affinity. Kinetic experiments in the presence of both molecular chaperones reveal that their inhibitory effects are additive and noncooperative, thereby indicating that the reactive sites associated with the formation of new aggregates and the growth of existing aggregates are distinct.

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Science Advances
volume
5
issue
4
publisher
American Association for the Advancement of Science (AAAS)
external identifiers
  • scopus:85064739477
ISSN
2375-2548
DOI
10.1126/sciadv.aau3112
language
English
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yes
id
78005d7f-c525-4b1f-9a06-d04c0e387b53
date added to LUP
2019-05-07 12:59:42
date last changed
2019-05-28 03:57:58
@article{78005d7f-c525-4b1f-9a06-d04c0e387b53,
  abstract     = {<p>The aggregates of the Ab peptide associated with Alzheimer's disease are able to both grow in size aswell as generate, through secondary nucleation, new small oligomeric species, that are major cytotoxins associated with neuronal death. Despite the importance of these amyloid fibril-dependent processes, their structural and molecular underpinnings have remained challenging to elucidate. Here, we consider two molecular chaperones: The Brichos domain, which suppresses specifically secondary nucleation processes, and clusterin which our results show is capable of inhibiting, specifically, the elongation of Ab fibrils at remarkably low substoichiometric ratios. Microfluidic diffusional sizing measurements demonstrate that this inhibition originates from interactions of clusterin with fibril ends with high affinity. Kinetic experiments in the presence of both molecular chaperones reveal that their inhibitory effects are additive and noncooperative, thereby indicating that the reactive sites associated with the formation of new aggregates and the growth of existing aggregates are distinct.</p>},
  articleno    = {eaau3112},
  author       = {Scheidt, Tom and Łapińska, Urszula and Kumita, Janet R. and Whiten, Daniel R. and Klenerman, David and Wilson, Mark R. and Cohen, Samuel I.A. and Linse, Sara and Vendruscolo, Michele and Dobson, Christopher M. and Knowles, Tuomas P.J. and Arosio, Paolo},
  issn         = {2375-2548},
  language     = {eng},
  number       = {4},
  publisher    = {American Association for the Advancement of Science (AAAS)},
  series       = {Science Advances},
  title        = {Secondary nucleation and elongation occur at different sites on Alzheimer's amyloid-b aggregates},
  url          = {http://dx.doi.org/10.1126/sciadv.aau3112},
  volume       = {5},
  year         = {2019},
}