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The Aggregation Paths and Products of Aβ42 Dimers Are Distinct from Those of the Aβ42 Monomer

O'Malley, Tiernan T.; Witbold, William M.; Linse, Sara LU and Walsh, Dominic M. (2016) In Biochemistry 55(44). p.6150-6161
Abstract

Extracts of Alzheimer's disease (AD) brain that contain what appear to be sodium dodecyl sulfate-stable amyloid β-protein (Aβ) dimers potently block LTP and impair memory consolidation. Brain-derived dimers can be physically separated the Aβ monomer, consist primarily of Aβ42, and resist denaturation by chaotropic agents. In nature, covalently cross-linked Aβ dimers could be generated in two ways: by the formation of a dityrosine (DiY) or an isopeptide ϵ-(γ-glutamyl)-lysine (Q-K) bond. We enzymatically cross-linked recombinant Aβ42 monomer to produce DiY and Q-K dimers and then used a range of biophysical methods to study their aggregation. Both Q-K and DiY dimers aggregate to form soluble assemblies distinct from the fibrillar... (More)

Extracts of Alzheimer's disease (AD) brain that contain what appear to be sodium dodecyl sulfate-stable amyloid β-protein (Aβ) dimers potently block LTP and impair memory consolidation. Brain-derived dimers can be physically separated the Aβ monomer, consist primarily of Aβ42, and resist denaturation by chaotropic agents. In nature, covalently cross-linked Aβ dimers could be generated in two ways: by the formation of a dityrosine (DiY) or an isopeptide ϵ-(γ-glutamyl)-lysine (Q-K) bond. We enzymatically cross-linked recombinant Aβ42 monomer to produce DiY and Q-K dimers and then used a range of biophysical methods to study their aggregation. Both Q-K and DiY dimers aggregate to form soluble assemblies distinct from the fibrillar aggregates formed by the Aβ monomer. The results suggest that the cross-links disfavor fibril formation from Aβ dimers, thereby enhancing the concentration of soluble aggregates akin to those in aqueous extracts of AD brain. Thus, it seems that Aβ dimers may play an important role in determining the formation of soluble rather than insoluble aggregates.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Biochemistry
volume
55
issue
44
pages
12 pages
publisher
The American Chemical Society
external identifiers
  • scopus:84994753080
ISSN
0006-2960
DOI
10.1021/acs.biochem.6b00453
language
English
LU publication?
yes
id
55db4fd6-359a-4531-a414-b228f0078f41
date added to LUP
2016-11-29 08:35:43
date last changed
2017-08-30 03:00:20
@article{55db4fd6-359a-4531-a414-b228f0078f41,
  abstract     = {<p>Extracts of Alzheimer's disease (AD) brain that contain what appear to be sodium dodecyl sulfate-stable amyloid β-protein (Aβ) dimers potently block LTP and impair memory consolidation. Brain-derived dimers can be physically separated the Aβ monomer, consist primarily of Aβ42, and resist denaturation by chaotropic agents. In nature, covalently cross-linked Aβ dimers could be generated in two ways: by the formation of a dityrosine (DiY) or an isopeptide ϵ-(γ-glutamyl)-lysine (Q-K) bond. We enzymatically cross-linked recombinant Aβ42 monomer to produce DiY and Q-K dimers and then used a range of biophysical methods to study their aggregation. Both Q-K and DiY dimers aggregate to form soluble assemblies distinct from the fibrillar aggregates formed by the Aβ monomer. The results suggest that the cross-links disfavor fibril formation from Aβ dimers, thereby enhancing the concentration of soluble aggregates akin to those in aqueous extracts of AD brain. Thus, it seems that Aβ dimers may play an important role in determining the formation of soluble rather than insoluble aggregates.</p>},
  author       = {O'Malley, Tiernan T. and Witbold, William M. and Linse, Sara and Walsh, Dominic M.},
  issn         = {0006-2960},
  language     = {eng},
  month        = {11},
  number       = {44},
  pages        = {6150--6161},
  publisher    = {The American Chemical Society},
  series       = {Biochemistry},
  title        = {The Aggregation Paths and Products of Aβ42 Dimers Are Distinct from Those of the Aβ42 Monomer},
  url          = {http://dx.doi.org/10.1021/acs.biochem.6b00453},
  volume       = {55},
  year         = {2016},
}