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Observation of β-Amyloid Peptide Oligomerization by Pressure-Jump NMR Spectroscopy

Barnes, C. Ashley ; Robertson, Angus J. LU ; Louis, John M. ; Anfinrud, Philip and Bax, Ad (2019) In Journal of the American Chemical Society 141(35). p.13762-13766
Abstract
Brain tissue of Alzheimer’s disease patients invariably contains deposits of insoluble, fibrillar aggregates of peptide fragments of the amyloid precursor protein (APP), typically 40 or 42 residues in length and referred to as Aβ40 and Aβ42. However, it remains unclear whether these fibrils or oligomers constitute the toxic species. Depending on sample conditions, oligomers can form in a few seconds or less. These oligomers are invisible to solution NMR spectroscopy, but they can be rapidly (<1 s) resolubilized and converted to their NMR-visible monomeric constituents by raising the hydrostatic pressure to a few kbar. Hence, utilizing pressure-jump NMR, the oligomeric state can be studied at residue-specific resolution by monitoring its... (More)
Brain tissue of Alzheimer’s disease patients invariably contains deposits of insoluble, fibrillar aggregates of peptide fragments of the amyloid precursor protein (APP), typically 40 or 42 residues in length and referred to as Aβ40 and Aβ42. However, it remains unclear whether these fibrils or oligomers constitute the toxic species. Depending on sample conditions, oligomers can form in a few seconds or less. These oligomers are invisible to solution NMR spectroscopy, but they can be rapidly (<1 s) resolubilized and converted to their NMR-visible monomeric constituents by raising the hydrostatic pressure to a few kbar. Hence, utilizing pressure-jump NMR, the oligomeric state can be studied at residue-specific resolution by monitoring its signals in the monomeric state. Oligomeric states of Aβ40 exhibit a high degree of order, reflected by slow longitudinal 15N relaxation (T1 > 5 s) for residues 18–21 and 31–34, whereas the N-terminal 10 residues relax much faster (T1 ≤ 1.5 s), indicative of extensive internal motions. Transverse relaxation rates rapidly increase to ca. 1000 s–1 after the oligomerization is initiated. (Less)
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author
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publishing date
type
Contribution to journal
publication status
published
in
Journal of the American Chemical Society
volume
141
issue
35
pages
13762 - 13766
publisher
The American Chemical Society (ACS)
external identifiers
  • scopus:85071788460
ISSN
1520-5126
DOI
10.1021/jacs.9b06970
language
English
LU publication?
no
id
5ac08dbe-5865-4322-bb1d-a91af8101d1c
date added to LUP
2024-01-25 13:26:21
date last changed
2024-01-29 10:10:29
@article{5ac08dbe-5865-4322-bb1d-a91af8101d1c,
  abstract     = {{Brain tissue of Alzheimer’s disease patients invariably contains deposits of insoluble, fibrillar aggregates of peptide fragments of the amyloid precursor protein (APP), typically 40 or 42 residues in length and referred to as Aβ40 and Aβ42. However, it remains unclear whether these fibrils or oligomers constitute the toxic species. Depending on sample conditions, oligomers can form in a few seconds or less. These oligomers are invisible to solution NMR spectroscopy, but they can be rapidly (&lt;1 s) resolubilized and converted to their NMR-visible monomeric constituents by raising the hydrostatic pressure to a few kbar. Hence, utilizing pressure-jump NMR, the oligomeric state can be studied at residue-specific resolution by monitoring its signals in the monomeric state. Oligomeric states of Aβ40 exhibit a high degree of order, reflected by slow longitudinal 15N relaxation (T1 &gt; 5 s) for residues 18–21 and 31–34, whereas the N-terminal 10 residues relax much faster (T1 ≤ 1.5 s), indicative of extensive internal motions. Transverse relaxation rates rapidly increase to ca. 1000 s–1 after the oligomerization is initiated.}},
  author       = {{Barnes, C. Ashley and Robertson, Angus J. and Louis, John M. and Anfinrud, Philip and Bax, Ad}},
  issn         = {{1520-5126}},
  language     = {{eng}},
  month        = {{09}},
  number       = {{35}},
  pages        = {{13762--13766}},
  publisher    = {{The American Chemical Society (ACS)}},
  series       = {{Journal of the American Chemical Society}},
  title        = {{Observation of β-Amyloid Peptide Oligomerization by Pressure-Jump NMR Spectroscopy}},
  url          = {{http://dx.doi.org/10.1021/jacs.9b06970}},
  doi          = {{10.1021/jacs.9b06970}},
  volume       = {{141}},
  year         = {{2019}},
}