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

Abstract

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:
Research Org.:
Brookhaven National Lab. (BNL), Upton, NY (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
OSTI Identifier:
1351799
Report Number(s):
BNL-113696-2017-JA
Journal ID: ISSN 0027-8424
Grant/Contract Number:  
SC00112704
Resource 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)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; amyloid; solid-state NMR; Alzheimer's disease; protein structure

Citation Formats

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., 2016. 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. Thu . "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}
}

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Works referenced in this record:

Amyloid plaque core protein in Alzheimer disease and Down syndrome.
journal, June 1985

  • Masters, C. L.; Simms, G.; Weinman, N. A.
  • Proceedings of the National Academy of Sciences, Vol. 82, Issue 12
  • DOI: 10.1073/pnas.82.12.4245

Alzheimer's disease and Down's syndrome: Sharing of a unique cerebrovascular amyloid fibril protein
journal, August 1984

  • Glenner, George G.; Wong, Caine W.
  • Biochemical and Biophysical Research Communications, Vol. 122, Issue 3
  • DOI: 10.1016/0006-291X(84)91209-9

The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor
journal, February 1987

  • Kang, Jie; Lemaire, Hans-Georg; Unterbeck, Axel
  • Nature, Vol. 325, Issue 6106
  • DOI: 10.1038/325733a0

The cell biology of prion-like spread of protein aggregates: mechanisms and implication in neurodegeneration
journal, April 2013

  • Costanzo, Maddalena; Zurzolo, Chiara
  • Biochemical Journal, Vol. 452, Issue 1
  • DOI: 10.1042/BJ20121898

The amyloid hypothesis of Alzheimer's disease at 25 years
journal, March 2016


beta-Amyloid-(1-42) is a major component of cerebrovascular amyloid deposits: implications for the pathology of Alzheimer disease.
journal, November 1993

  • Roher, A. E.; Lowenson, J. D.; Clarke, S.
  • Proceedings of the National Academy of Sciences, Vol. 90, Issue 22
  • DOI: 10.1073/pnas.90.22.10836

Alzheimer's Disease: A Central Role for Amyloid
journal, September 1994


Amyloid β Protein (Aβ) in Alzheimeri's Disease Brain: BIOCHEMICAL AND IMMUNOCYTOCHEMICAL ANALYSIS WITH ANTIBODIES SPECIFIC FOR FORMS ENDING AT Aβ40 OR Aβ42(43)
journal, March 1995

  • Gravina, Stephen A.; Ho, Libin; Eckman, Christopher B.
  • Journal of Biological Chemistry, Vol. 270, Issue 13
  • DOI: 10.1074/jbc.270.13.7013

The structure of fibrils from ‘misfolded’ proteins
journal, February 2015


The carboxy terminus of the .beta. amyloid protein is critical for the seeding of amyloid formation: Implications for the pathogenesis of Alzheimer's disease
journal, May 1993

  • Jarrett, Joseph T.; Berger, Elizabeth P.; Lansbury, Peter T.
  • Biochemistry, Vol. 32, Issue 18
  • DOI: 10.1021/bi00069a001

The C-Terminus of the β Protein is Critical in Amyloidogenesisa
journal, September 1993


Oligomerization and Toxicity of β-Amyloid-42 Implicated in Alzheimer's Disease
journal, July 2000

  • El-Agnaf, Omar M. A.; Mahil, Devinder S.; Patel, Bhroma P.
  • Biochemical and Biophysical Research Communications, Vol. 273, Issue 3
  • DOI: 10.1006/bbrc.2000.3051

A New Structural Model of Aβ 40 Fibrils
journal, October 2011

  • Bertini, Ivano; Gonnelli, Leonardo; Luchinat, Claudio
  • Journal of the American Chemical Society, Vol. 133, Issue 40
  • DOI: 10.1021/ja2035859

A structural model for Alzheimer's  -amyloid fibrils based on experimental constraints from solid state NMR
journal, December 2002

  • Petkova, A. T.; Ishii, Y.; Balbach, J. J.
  • Proceedings of the National Academy of Sciences, Vol. 99, Issue 26
  • DOI: 10.1073/pnas.262663499

Experimental Constraints on Quaternary Structure in Alzheimer's β-Amyloid Fibrils
journal, January 2006

  • Petkova, Aneta T.; Yau, Wai-Ming; Tycko, Robert
  • Biochemistry, Vol. 45, Issue 2
  • DOI: 10.1021/bi051952q

Atomic-Resolution Three-Dimensional Structure of Amyloid β Fibrils Bearing the Osaka Mutation
journal, November 2014

  • Schütz, Anne K.; Vagt, Toni; Huber, Matthias
  • Angewandte Chemie International Edition, Vol. 54, Issue 1
  • DOI: 10.1002/anie.201408598

3D structure of Alzheimer's amyloid- (1-42) fibrils
journal, November 2005

  • Luhrs, T.; Ritter, C.; Adrian, M.
  • Proceedings of the National Academy of Sciences, Vol. 102, Issue 48
  • DOI: 10.1073/pnas.0506723102

Amide solvent protection analysis demonstrates that amyloid-β(1–40) and amyloid-β(1–42) form different fibrillar structures under identical conditions
journal, April 2007

  • Olofsson, Anders; Lindhagen-Persson, Malin; Sauer-Eriksson, A. Elisabeth
  • Biochemical Journal, Vol. 404, Issue 1
  • DOI: 10.1042/BJ20061561

X-ray diffraction from intraneuronal paired helical filaments and extraneuronal amyloid fibers in Alzheimer disease indicates cross-beta conformation.
journal, January 1986

  • Kirschner, D. A.; Abraham, C.; Selkoe, D. J.
  • Proceedings of the National Academy of Sciences, Vol. 83, Issue 2
  • DOI: 10.1073/pnas.83.2.503

Common core structure of amyloid fibrils by synchrotron X-ray diffraction 1 1Edited by F. E. Cohen
journal, October 1997

  • Sunde, Margaret; Serpell, Louise C.; Bartlam, Mark
  • Journal of Molecular Biology, Vol. 273, Issue 3
  • DOI: 10.1006/jmbi.1997.1348

Peptide dimer structure in an Aβ(1–42) fibril visualized with cryo-EM
journal, September 2015

  • Schmidt, Matthias; Rohou, Alexis; Lasker, Keren
  • Proceedings of the National Academy of Sciences, Vol. 112, Issue 38
  • DOI: 10.1073/pnas.1503455112

Structural conversion of neurotoxic amyloid-β1–42 oligomers to fibrils
journal, April 2010

  • Ahmed, Mahiuddin; Davis, Judianne; Aucoin, Darryl
  • Nature Structural & Molecular Biology, Vol. 17, Issue 5
  • DOI: 10.1038/nsmb.1799

Analysis of the Secondary Structure of β-Amyloid (Aβ42) Fibrils by Systematic Proline Replacement
journal, September 2004

  • Morimoto, Akira; Irie, Kazuhiro; Murakami, Kazuma
  • Journal of Biological Chemistry, Vol. 279, Issue 50
  • DOI: 10.1074/jbc.M406262200

Structure of the cross-β spine of amyloid-like fibrils
journal, June 2005

  • Nelson, Rebecca; Sawaya, Michael R.; Balbirnie, Melinda
  • Nature, Vol. 435, Issue 7043
  • DOI: 10.1038/nature03680

Supramolecular Structural Constraints on Alzheimer's β-Amyloid Fibrils from Electron Microscopy and Solid-State Nuclear Magnetic Resonance
journal, December 2002

  • Antzutkin, Oleg N.; Leapman, Richard D.; Balbach, John J.
  • Biochemistry, Vol. 41, Issue 51
  • DOI: 10.1021/bi0204185

Aβ(1–42) fibril structure illuminates self-recognition and replication of amyloid in Alzheimer's disease
journal, May 2015

  • Xiao, Yiling; Ma, Buyong; McElheny, Dan
  • Nature Structural & Molecular Biology, Vol. 22, Issue 6
  • DOI: 10.1038/nsmb.2991

Structural polymorphism of Alzheimer Aβ and other amyloid fibrils
journal, April 2009

  • Fändrich, Marcus; Meinhardt, Jessica; Grigorieff, Nikolaus
  • Prion, Vol. 3, Issue 2
  • DOI: 10.4161/pri.3.2.8859

Molecular basis for amyloid-  polymorphism
journal, September 2011

  • Colletier, J. -P.; Laganowsky, A.; Landau, M.
  • Proceedings of the National Academy of Sciences, Vol. 108, Issue 41
  • DOI: 10.1073/pnas.1112600108

Structural and functional characterization of two alpha-synuclein strains
journal, October 2013

  • Bousset, Luc; Pieri, Laura; Ruiz-Arlandis, Gemma
  • Nature Communications, Vol. 4, Issue 1
  • DOI: 10.1038/ncomms3575

Unlike Twins: An NMR Comparison of Two α-Synuclein Polymorphs Featuring Different Toxicity
journal, March 2014


13C–1H dipolar-assisted rotational resonance in magic-angle spinning NMR
journal, August 2001


13C–1H dipolar-driven 13C–13C recoupling without 13C rf irradiation in nuclear magnetic resonance of rotating solids
journal, February 2003

  • Takegoshi, K.; Nakamura, Shinji; Terao, Takehiko
  • The Journal of Chemical Physics, Vol. 118, Issue 5
  • DOI: 10.1063/1.1534105

Conformation dependent monoclonal antibodies distinguish different replicating strains or conformers of prefibrillar Aβ oligomers
journal, January 2010

  • Kayed, Rakez; Canto, Isabel; Breydo, Leonid
  • Molecular Neurodegeneration, Vol. 5, Issue 1
  • DOI: 10.1186/1750-1326-5-57

Monoclonal Antibodies against Aβ42 Fibrils Distinguish Multiple Aggregation State Polymorphisms in Vitro and in Alzheimer Disease Brain
journal, October 2014

  • Hatami, Asa; Albay, Ricardo; Monjazeb, Sanaz
  • Journal of Biological Chemistry, Vol. 289, Issue 46
  • DOI: 10.1074/jbc.M114.594846

Structure and mass analysis by scanning transmission electron microscopy
journal, January 2001


Mass analysis of biological macromolecular complexes by STEM
journal, January 1994


Solid-state NMR sequential assignment of an Amyloid-β(1–42) fibril polymorph
journal, May 2016

  • Ravotti, Francesco; Wälti, Marielle Aulikki; Güntert, Peter
  • Biomolecular NMR Assignments, Vol. 10, Issue 2
  • DOI: 10.1007/s12104-016-9682-y

TALOS+: a hybrid method for predicting protein backbone torsion angles from NMR chemical shifts
journal, June 2009

  • Shen, Yang; Delaglio, Frank; Cornilescu, Gabriel
  • Journal of Biomolecular NMR, Vol. 44, Issue 4
  • DOI: 10.1007/s10858-009-9333-z

Proton Assisted Insensitive Nuclei Cross Polarization
journal, January 2007

  • Lewandowski, Józef R.; De Paëpe, Gaël; Griffin, Robert G.
  • Journal of the American Chemical Society, Vol. 129, Issue 4
  • DOI: 10.1021/ja0650394

3D TEDOR NMR Experiments for the Simultaneous Measurement of Multiple Carbon−Nitrogen Distances in Uniformly 13 C, 15 N-Labeled Solids
journal, September 2002

  • Jaroniec, Christopher P.; Filip, Claudiu; Griffin, Robert G.
  • Journal of the American Chemical Society, Vol. 124, Issue 36
  • DOI: 10.1021/ja026385y

Transferred-echo double-resonance NMR
journal, January 1992


Statistical Basis for the Use of13CαChemical Shifts in Protein Structure Determination
journal, November 1995

  • Luginbühl, Peter; Szyperski, Thomas; Wüthrich, Kurt
  • Journal of Magnetic Resonance, Series B, Vol. 109, Issue 2
  • DOI: 10.1006/jmrb.1995.0016

The 13C Chemical-Shift Index: A simple method for the identification of protein secondary structure using 13C chemical-shift data
journal, March 1994

  • Wishart, DavidS.; Sykes, BrianD.
  • Journal of Biomolecular NMR, Vol. 4, Issue 2
  • DOI: 10.1007/BF00175245

The chemical shift index: a fast and simple method for the assignment of protein secondary structure through NMR spectroscopy
journal, February 1992

  • Wishart, D. S.; Sykes, B. D.; Richards, F. M.
  • Biochemistry, Vol. 31, Issue 6
  • DOI: 10.1021/bi00121a010

Structural Constraints from Proton-Mediated Rare-Spin Correlation Spectroscopy in Rotating Solids
journal, August 2002

  • Lange, Adam; Luca, Sorin; Baldus, Marc
  • Journal of the American Chemical Society, Vol. 124, Issue 33
  • DOI: 10.1021/ja026691b

Proton assisted recoupling and protein structure determination
journal, December 2008

  • De Paëpe, Gaël; Lewandowski, Józef R.; Loquet, Antoine
  • The Journal of Chemical Physics, Vol. 129, Issue 24
  • DOI: 10.1063/1.3036928

Torsion angle dynamics for NMR structure calculation with the new program Dyana
journal, October 1997

  • Güntert, P.; Mumenthaler, C.; Wüthrich, K.
  • Journal of Molecular Biology, Vol. 273, Issue 1
  • DOI: 10.1006/jmbi.1997.1284

Combined automated NOE assignment and structure calculation with CYANA
journal, March 2015


Contribution of Specific Residues of the β-Solenoid Fold to HET-s Prion Function, Amyloid Structure and Stability
journal, June 2014


Amyloid Fibrils of the HET-s(218-289) Prion Form a   Solenoid with a Triangular Hydrophobic Core
journal, March 2008


High Resolution Structural Characterization of Aβ 42 Amyloid Fibrils by Magic Angle Spinning NMR
journal, June 2015

  • Colvin, Michael T.; Silvers, Robert; Frohm, Birgitta
  • Journal of the American Chemical Society, Vol. 137, Issue 23
  • DOI: 10.1021/jacs.5b03997

Infectious Alzheimer's disease?
journal, November 2006


Exogenous Induction of Cerebral  -Amyloidogenesis Is Governed by Agent and Host
journal, September 2006


Solution NMR Studies of Recombinant Aβ(1-42): From the Presence of a Micellar Entity to Residual β-Sheet Structure in the Soluble Species
journal, February 2015

  • Wälti, Marielle Aulikki; Orts, Julien; Vögeli, Beat
  • ChemBioChem, Vol. 16, Issue 4
  • DOI: 10.1002/cbic.201402595

Characterization of different water pools in solid-state NMR protein samples
journal, September 2009

  • Böckmann, Anja; Gardiennet, Carole; Verel, René
  • Journal of Biomolecular NMR, Vol. 45, Issue 3
  • DOI: 10.1007/s10858-009-9374-3

The CCPN data model for NMR spectroscopy: Development of a software pipeline
journal, April 2005

  • Vranken, Wim F.; Boucher, Wayne; Stevens, Tim J.
  • Proteins: Structure, Function, and Bioinformatics, Vol. 59, Issue 4
  • DOI: 10.1002/prot.20449

Annular Protofibrils Are a Structurally and Functionally Distinct Type of Amyloid Oligomer
journal, December 2008

  • Kayed, Rakez; Pensalfini, Anna; Margol, Larry
  • Journal of Biological Chemistry, Vol. 284, Issue 7
  • DOI: 10.1074/jbc.M808591200

Acquisition of chemiluminescent signals from immunoblots with a digital single-lens reflex camera
journal, February 2010

  • Khoury, Mitri K.; Parker, Ian; Aswad, Dana W.
  • Analytical Biochemistry, Vol. 397, Issue 1
  • DOI: 10.1016/j.ab.2009.09.041

Atomic-Resolution Three-Dimensional Structure of HET-s(218−289) Amyloid Fibrils by Solid-State NMR Spectroscopy
journal, October 2010

  • Van Melckebeke, Hélène; Wasmer, Christian; Lange, Adam
  • Journal of the American Chemical Society, Vol. 132, Issue 39
  • DOI: 10.1021/ja104213j

Influence of 1H chemical shift assignments of the interface residues on structure determinations of homodimeric proteins
journal, September 2012


Increased Reliability of Nuclear Magnetic Resonance Protein Structures by Consensus Structure Bundles
journal, February 2015


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