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Title: Atomic-resolution structure of a disease-relevant Aβ(1–42) amyloid fibril

Amyloid-β (Aβ) is present in humans as a 39- to 42-amino acid residue metabolic product of the amyloid precursor protein. Although the two predominant forms, Aβ(1–40) and Aβ(1–42), differ in only two residues, they display different biophysical, biological, and clinical behavior. Aβ(1–42) is the more neurotoxic species, aggregates much faster, and dominates in senile plaque of Alzheimer’s disease (AD) patients. Although small Aβ oligomers are believed to be the neurotoxic species, Aβ amyloid fibrils are, because of their presence in plaques, a pathological hallmark of AD and appear to play an important role in disease progression through cell-to-cell transmissibility. Here, we solved the 3D structure of a disease-relevant Aβ(1–42) fibril polymorph, combining data from solid-state NMR spectroscopy and mass-per-length measurements from EM. The 3D structure is composed of two molecules per fibril layer, with residues 15–42 forming a double-horseshoe–like cross–β-sheet entity with maximally buried hydrophobic side chains. Lastly, residues 1–14 are partially ordered and in a β-strand conformation, but do not display unambiguous distance restraints to the remainder of the core structure.
Authors:
 [1] ;  [1] ;  [2] ;  [3] ;  [4] ;  [5] ;  [6] ;  [1] ;  [1]
  1. Eidgenossische Technische Hochschule Zurich, Zurich (Switzerland)
  2. Univ. of California, Irvine, CA (United States)
  3. Univ. of California, Irvine, CA (United States); King Abdulaziz Univ., Jeddah (Saudi Arabia)
  4. King Abdulaziz Univ., Jeddah (Saudi Arabia)
  5. Univ. de Lyon, Lyon (France)
  6. Eidgenossische Technische Hochschule Zurich, Zurich (Switzerland); Goethe Univ. Frankfurt am Main, Frankfurt am Main (Germany); Tokyo Metropolitan Univ., Tokyo (Japan)
Publication Date:
Report Number(s):
BNL-113696-2017-JA
Journal ID: ISSN 0027-8424
Grant/Contract Number:
SC00112704
Type:
Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 113; Journal Issue: 34; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)
Research Org:
Brookhaven National Laboratory (BNL), Upton, NY (United States)
Sponsoring Org:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; amyloid; solid-state NMR; Alzheimer's disease; protein structure
OSTI Identifier:
1351799

Wälti, Marielle Aulikki, Ravotti, Francesco, Arai, Hiromi, Glabe, Charles G., Wall, Joseph S., Böckmann, Anja, Güntert, Peter, Meier, Beat H., and Riek, Roland. Atomic-resolution structure of a disease-relevant Aβ(1–42) amyloid fibril. United States: N. p., Web. doi:10.1073/pnas.1600749113.
Wälti, Marielle Aulikki, Ravotti, Francesco, Arai, Hiromi, Glabe, Charles G., Wall, Joseph S., Böckmann, Anja, Güntert, Peter, Meier, Beat H., & Riek, Roland. Atomic-resolution structure of a disease-relevant Aβ(1–42) amyloid fibril. United States. doi:10.1073/pnas.1600749113.
Wälti, Marielle Aulikki, Ravotti, Francesco, Arai, Hiromi, Glabe, Charles G., Wall, Joseph S., Böckmann, Anja, Güntert, Peter, Meier, Beat H., and Riek, Roland. 2016. "Atomic-resolution structure of a disease-relevant Aβ(1–42) amyloid fibril". United States. doi:10.1073/pnas.1600749113. https://www.osti.gov/servlets/purl/1351799.
@article{osti_1351799,
title = {Atomic-resolution structure of a disease-relevant Aβ(1–42) amyloid fibril},
author = {Wälti, Marielle Aulikki and Ravotti, Francesco and Arai, Hiromi and Glabe, Charles G. and Wall, Joseph S. and Böckmann, Anja and Güntert, Peter and Meier, Beat H. and Riek, Roland},
abstractNote = {Amyloid-β (Aβ) is present in humans as a 39- to 42-amino acid residue metabolic product of the amyloid precursor protein. Although the two predominant forms, Aβ(1–40) and Aβ(1–42), differ in only two residues, they display different biophysical, biological, and clinical behavior. Aβ(1–42) is the more neurotoxic species, aggregates much faster, and dominates in senile plaque of Alzheimer’s disease (AD) patients. Although small Aβ oligomers are believed to be the neurotoxic species, Aβ amyloid fibrils are, because of their presence in plaques, a pathological hallmark of AD and appear to play an important role in disease progression through cell-to-cell transmissibility. Here, we solved the 3D structure of a disease-relevant Aβ(1–42) fibril polymorph, combining data from solid-state NMR spectroscopy and mass-per-length measurements from EM. The 3D structure is composed of two molecules per fibril layer, with residues 15–42 forming a double-horseshoe–like cross–β-sheet entity with maximally buried hydrophobic side chains. Lastly, residues 1–14 are partially ordered and in a β-strand conformation, but do not display unambiguous distance restraints to the remainder of the core structure.},
doi = {10.1073/pnas.1600749113},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 34,
volume = 113,
place = {United States},
year = {2016},
month = {7}
}