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Structure-specific amyloid precipitation in biofluids

Nature Chemistry volume 14, pages 1045–1053 (2022)Cite this article

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Abstract

The composition of soluble toxic protein aggregates formed in vivo is currently unknown in neurodegenerative diseases, due to their ultra-low concentration in human biofluids and their high degree of heterogeneity. Here we report a method to capture amyloid-containing aggregates in human biofluids in an unbiased way, a process we name amyloid precipitation. We use a structure-specific chemical dimer, a Y-shaped, bio-inspired small molecule with two capture groups, for amyloid precipitation to increase affinity. Our capture molecule for amyloid precipitation (CAP-1) consists of a derivative of Pittsburgh Compound B (dimer) to target the cross β-sheets of amyloids and a biotin moiety for surface immobilization. By coupling CAP-1 to magnetic beads, we demonstrate that we can target the amyloid structure of all protein aggregates present in human cerebrospinal fluid, isolate them for analysis and then characterize them using single-molecule fluorescence imaging and mass spectrometry. Amyloid precipitation enables unbiased determination of the molecular composition and structural features of the in vivo aggregates formed in neurodegenerative diseases.

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Fig. 1: Design and characterization of a bio-inspired structure-specific chemical dimer.
Fig. 2: AP using CAP-1.
Fig. 3: AP of CSF spiked with recombinant α-synuclein oligomers.

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Data availability

The data supporting the findings of this study are available within the paper and its Supplementary Information. The data are also available from the corresponding authors on reasonable request. We used the Swiss-Prot database to identify the proteins present in the MS samples. Source data are provided with this paper.

Code availability

The custom Matlab code used for analysis of the proteins is available on GitHub: https://github.com/TheLeeLab/Nature-Chemisty-2022-Structure-specific-amyloid-precipitation-in-biofluids.

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Acknowledgements

This work was supported by the National Institute of Health Research University College London Hospitals Biomedical Research Centre. SG is an MRC Senior Clinical Fellow (MR/T008199/1). H.Z. is a Wallenberg Scholar supported by grants from the Swedish Research Council (no. 2018-02532), the European Research Council (no. 681712), Swedish State Support for Clinical Research (no. ALFGBG-720931) and the UK Dementia Research Institute at University College London (UCL). D.K. is supported by grants from the European Research Council (no. 669237), the Royal Society and the UK Dementia Research Institute at Cambridge. We thank the Royal Society for the University Research Fellowship to S.F.L. (UF120277), and T.N.S. thanks the National Institutes of Health (R01GM121573). Also, we are thankful for the Michael J. Fox Grant to S.F.L. and T.N.S. (grant no. 10200). J.A.V. is supported by the European Research Council with an ERC Starting Grant (no. 804581).

Author information

Authors and Affiliations

  1. Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK

    M. Rodrigues, S. De, A. Ponjavic, J. A. Varela, K. Kulenkampff, I. Baudrexel, D. Emin, F. S. Ruggeri, J. E. Lee, A. R. Carr, T. P. J. Knowles, S. F. Lee & D. Klenerman

  2. UK Dementia Research Institute, University of Cambridge, Cambridge, UK

    M. Rodrigues, S. De, K. Kulenkampff, D. Emin & D. Klenerman

  3. Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden

    P. Bhattacharjee, A. Brinkmalm & H. Zetterberg

  4. Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden

    P. Bhattacharjee, A. Brinkmalm & H. Zetterberg

  5. Department of Chemistry, Indiana University, Bloomington, IN, USA

    D. T. Do, C. M. Pearson & T. N. Snaddon

  6. Sheffield Institute for Translational Neuroscience, University of Sheffield, Western Bank, Sheffield, UK

    S. De

  7. School of Physics and Astronomy, University of Leeds, Leeds, UK

    A. Ponjavic

  8. School of Food Science and Nutrition, University of Leeds, Leeds, UK

    A. Ponjavic

  9. School of Physics and Astronomy, University of St Andrews, St Andrews, UK

    J. A. Varela

  10. Laboratory of Organic Chemistry, Wageningen University & Research, Wageningen, The Netherlands

    F. S. Ruggeri

  11. Physical Chemistry and Soft Matter, Wageningen University & Research, Wageningen, The Netherlands

    F. S. Ruggeri

  12. School of Chemistry, University of Edinburgh, Edinburgh, UK

    J. E. Lee

  13. Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK

    H. Zetterberg & S. Gandhi

  14. UK Dementia Research Institute, UCL, London, UK

    H. Zetterberg

  15. The Francis Crick Institute, London, UK

    S. Gandhi

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Contributions

S.F.L. and T.N.S. designed the CAP-1, and D.T.D. and C.M.P. synthesized the CAP-1. M.R. performed all the experiments with CAP-1 alongside with J.A.V. for the imaging experiments and analysis, I.B. for the pull-down essay, D.E. for the binding affinity experiments and J.E.L. for the bead imaging. A.P. and A.R.C. helped with imaging analysis, and K.K. prepared the Aβ42 and tau aggregates. S.D. performed the liposome assays, and F.S.R. performed the AFM measurements. H.Z. directed the MS studies, and M.R., P.B. and A.B. designed and performed the experiments and data analysis. S.F.L., S.G. and D.K. directed the research. M.R. wrote the first manuscript of the paper, and all authors contributed to the discussion and final manuscript.

Corresponding authors

Correspondence to T. N. Snaddon, S. Gandhi, S. F. Lee or D. Klenerman.

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Competing interests

H.Z. has served at scientific advisory boards for Roche Diagnostics, Wave, Samumed and CogRx; has given lectures in symposia sponsored by Alzecure and Biogen; and is a cofounder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg (outside of the submitted work). The remaining authors declare no competing interests.

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Nature Chemistry thanks Wolfgang Hoyer and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–25, Tables 1–9 and Methods.

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Supplementary Data 1

Numerical data for Supplementary Figs. 10–13, 15–18, 23 and 24.

Source data

Source Data Fig. 1

Numerical data for plots (Fig. 1d,e).

Source Data Fig. 2

Numerical data for plots (Fig. 2d,e).

Source Data Fig. 3

Numerical data for plots (Fig. 3b,d,e).

Source Data Fig. 1c

Microscopy image for Fig. 1c.

Source Data Fig. 2c

Microscopy image for Fig. 2c.

Source Data Fig. 3f

Microscopy image for Fig. 3f.

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Rodrigues, M., Bhattacharjee, P., Brinkmalm, A. et al. Structure-specific amyloid precipitation in biofluids. Nat. Chem. 14, 1045–1053 (2022). https://doi.org/10.1038/s41557-022-00976-3

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