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

Nature Structural & Molecular Biology volume 22, pages 499–505 (2015)Cite this article

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Abstract

Increasing evidence has suggested that formation and propagation of misfolded aggregates of 42-residue human amyloid β (Aβ(1–42)), rather than of the more abundant Aβ(1–40), provokes the Alzheimer's disease cascade. However, structural details of misfolded Aβ(1–42) have remained elusive. Here we present the atomic model of an Aβ(1–42) amyloid fibril, from solid-state NMR (ssNMR) data. It displays triple parallel-β-sheet segments that differ from reported structures of Aβ(1–40) fibrils. Remarkably, Aβ(1–40) is incompatible with the triple-β-motif, because seeding with Aβ(1–42) fibrils does not promote conversion of monomeric Aβ(1–40) into fibrils via cross-replication. ssNMR experiments suggest that C-terminal Ala42, absent in Aβ(1–40), forms a salt bridge with Lys28 to create a self-recognition molecular switch that excludes Aβ(1–40). The results provide insight into the Aβ(1–42)-selective self-replicating amyloid-propagation machinery in early-stage Alzheimer's disease.

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Figure 1: Structural homogeneity and morphologies analysis of Aβ(1–42) amyloid fibrils.
Figure 2: ssNMR-based structural constraints for the Aβ(1–42) fibril.
Figure 3: Structural details of the Aβ(1–42) fibril revealed by the ssNMR analysis.
Figure 4: Cross-propagation kinetics of Aβ(1–40) monomers incubated with the seed Aβ(1–42) fibrils.

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Acknowledgements

This work was supported primarily by the US National Institutes of Health (NIH) RO1 program (GM 098033) and by an Alzheimer's Association Investigator-Initiated Research Grant (IIRG) (08-91256) to Y.I. This project has been funded in part with federal funds from the Frederick National Laboratory for Cancer Research, NIH, under contract HHSN261200800001E, to B.M. and R.N. This research was supported in part by the Intramural Research Program of the NIH, Frederick National Laboratory, Center for Cancer Research, to B.M. and R.N. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. MD simulations to generate initial structural models were performed at the high-performance computational facilities of the Biowulf PC/Linux cluster at the NIH (http://biowulf.nih.gov/). Y.I. is grateful to S. Chimon, C. Jones and N. Wickramasinghe for their initial efforts in the preparation of Aβ(1–42) fibrils at the University of Illinois at Chicago.

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Authors and Affiliations

  1. Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois, USA

    Yiling Xiao, Dan McElheny, Sudhakar Parthasarathy, Fei Long & Yoshitaka Ishii

  2. Cancer and Inflammation Program, Leidos Biomedical Research, National Cancer Institute at Frederick, Frederick, Maryland, USA

    Buyong Ma & Ruth Nussinov

  3. Institute of Biomedical Research and Innovation, Kobe, Japan

    Minako Hoshi

  4. Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Minako Hoshi

  5. Department of Human Genetics and Molecular Medicine, Sackler Institute of Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    Ruth Nussinov

  6. Center for Structural Biology, University of Illinois at Chicago, Chicago, Illinois, USA

    Yoshitaka Ishii

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Contributions

Y.X. and Y.I. designed the overall study and analyzed the data. Y.X., S.P., F.L., M.H. and Y.I. contributed to establishing sample-preparation procedures. Y.X. prepared the Aβ(1–42) fibril samples for the study with the help of S.P. and F.L. and with the advice of Y.I. Y.X. and Y.I. performed ssNMR experiments. Y.X. performed EM experiments with staff assistance from the University of Illinois at Chicago Research Resource Center. Y.X. and F.L. designed and performed kinetics experiments with ThT fluorescence spectroscopy. B.M., D.M., R.N. and Y.I. contributed to structural modeling and design. Y.X., D.M., B.M., R.N. and Y.I. wrote the paper. All authors were involved in the editing of the manuscript.

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Correspondence to Yoshitaka Ishii.

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Integrated supplementary information

Supplementary Figure 1 Identification of polymorphs and secondary structure.

(a) A comparison of the aliphatic spectral regions of 2D 13C–13C correlation spectra for non-seeded Aβ(1–42) fibril (G1 black) and Aβ(1–42) fibril obtained by 3 successive seeded incubations (G4 red) with slices along the indicated positions 1–4, which display cross peaks. The non-seeded fibril sample shows another set of cross peaks corresponding to the second conformer (black dotted circles) for Ala21, Val24, and Leu34 (assigned with blue arrows and labels). The seeded fibrils sample shows single set of cross peak for Phe20, Ala21, Val24 and Gly25 (assigned with black arrows and labels). Although Leu34 still displays a weak peak for the second set of cross peaks, it is clear that the secondary species was nearly completely suppressed by seeding. The base contour levels were set to (black) 5% and (red) 4% of the diagonal signal for 13Cα of Ala21, which both correspond to 4 times the root-mean-squared noise level. (b) Secondary 13C chemical shifts for 13Cα (red), 13Cβ (blue), 13CO (white) observed for the Aβ(1–42) fibrils by ssNMR. The secondary-shift value represents a deviation of the 13C shift from that for the corresponding amino acid for a model peptide in a random coil conformation. The orange diamonds denote the residue that does not exhibit a combination of negative 13Cα and positive 13Cβ secondary shifts, which is typical for a β-strand. (c) Dihedral angles (ϕ, ψ) obtained by TALOS-N analysis according to 13C, 15N, chemical shift analysis (Supplementary Table 1) of Aβ(1–42) in fibrils assemblies. The secondary structure analysis by the TALOS software indicated three extended β-strand regions (cyan arrows and cyan shadow) separated by loop/turn regions (black wave) at the residues of 21–26 and 33–35 as shown at the top of (b).

Supplementary Figure 2 Interstrand distance analyses and long-range intermolecular contacts in 2D 13C-13C ssNMR.

(a) Signal dephasing curves by fpRFDR-CT experiments for determination of an inter-β-strand 13CO–13CO distance for seeded Aβ(1–42) fibril sample (G4), with 13CO labeled at Ala30 (black circle) and Leu34 (green circle), respectively. The interstrand distances at Ala30 and Leu34 were both found to be 5.0 Å ± 0.1 Å. The results indicate an in-register parallel β-sheet arrangement. (b-d) Identification of inter-molecular cross peaks by a comparison of 2D 13C-13C DARR spectra of (red) a 50%-isotope-labeled Aβ(1–42) fibril sample and (black) a control sample made from 100% labeled Aβ(1–42) for a 200-ms mixing time. The 50%-labeled seeded Aβ(1–42) fibril sample (G4) was prepared by incubating from a 1: 1 mixture of unlabeled Aβ(1–42) peptide and Aβ(1–42) that was labeled with uniformly 13C-, 15N-labeled amino acids at residue Gly29 and Ile41 (b), Phe19, Ala30, Ile31, Gly33, and Val36 (c), and Phe20, Ala21, Val24, Gly25, and Leu34 (d). The data were apodized with a Lorentz-to-Gauss window function with an inverse exponential of 50 Hz and a Gaussian broadening of 130 Hz in both the t1 and t2 domains. The base contour levels were at 4–5 times the root-mean-squared noise level; the base levels correspond to (b) 5%, (c) 12%, (d) 11% (black) and (b) 4%, (c) 11%, (d) 5% (red) of the diagonal signal for 13Cα of (b) Ile41, (c) Ala30, and (d) Ala21. The purple arrows in the slices indicate long-range intra-molecular cross peaks, for which 50% “dilution” of 13C does not reduce the peak intensities more than 35%. Weak signals below the contour levels were not used for the quantitative analysis. The experimental time was (b) 3 and (c, d) 2 days for the 100% labeled sample, while that is (b) 4, (c) 2, and (d) 5 days for the 50% labeled sample.

Supplementary Figure 3 Overlaid ten best-fit atomic structure models of the Aβ(1–42) fibril.

The molecules at the edge and the N-terminal side chains at residues 11–15 were omitted for clarity.

Supplementary Figure 4 A comparison of previously published structural models for Aβ fibrils.

(a–c) Various atomic models of Aβ(1–40) fibrils (top) for a single protofilament unit and (bottom) multiple units. (d) A hypothetical structural model for Aβ(1–42) fibril. All the models were built from the pdb structures indicated in the figure. Experimentally observed side-chain contacts are denoted by orange dotted lines. All of the models share a U-shaped β-loop-β or β-turn-β structural motif with common contacts such as F19–L34 and D23–K28. For (d), side-chain contacts were deduced from pair-wise mutations, but no contacts were experimentally confirmed. PDB identifiers are indicated with the labels.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4, Supplementary Tables 1–8 and Supplementary Note (PDF 1377 kb)

Supplementary Data Set 1

Data set for 13C-15N REDOR distance measurement for K28-A42 (XLSX 14 kb)

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Xiao, Y., Ma, B., McElheny, D. et al. Aβ(1–42) fibril structure illuminates self-recognition and replication of amyloid in Alzheimer's disease. Nat Struct Mol Biol 22, 499–505 (2015). https://doi.org/10.1038/nsmb.2991

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