Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Ultraviolet–visible–near-infrared optical properties of amyloid fibrils shed light on amyloidogenesis

Abstract

Amyloid fibres attract considerable interest due to their biological role in neurodegenerative diseases and their potential as functional biomaterials. Here, we describe an intrinsic signal of amyloid fibres in the near-infrared range. When combined with their recently reported blue luminescence, it paves the way towards new blueprints for the label-free detection of amyloid deposits in in vitro and in vivo contexts. The blue luminescence allows for staining-free characterization of amyloid deposits in human samples. The near-infrared signal offers promising prospects for innovative diagnostic strategies for neurodegenerative diseases—to improve medical care and for the development of new therapies. As a proof of concept, we demonstrate direct detection of amyloid deposits within brains of living, aged mice with Alzheimer’s disease using non-invasive and contrast-agent-free imaging. Ultraviolet–visible–near-infrared optical properties of amyloids open new research avenues for amyloidosis as well as for next-generation biophotonic devices.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: UV–vis–NIR luminescence of Het-s prion domain and Aβ1–42 amyloid fibres.
Fig. 2: Luminescence properties of insulin amyloid protein during fibre growth process.
Fig. 3: Ex vivo confocal microscopy images of amyloid deposits in brain slices from pateints with Alzheimer’s disease within the hippocampus area.
Fig. 4: Detection of amyloid deposits by 3D NIR imaging in mice with Alzheimer’s disease and control mice.
Fig. 5: Non-invasive detection of amyloid deposits by 2D NIR imaging using Fluobeam800.

Data availability

The data that support the plots within this paper and other findings of this study are available from the corresponding author upon reasonable request.

References

  1. 1.

    Eisenberg, D. & Jucker, M. The amyloid state of proteins in human diseases. Cell 148, 1188–1203 (2012).

    Article  Google Scholar 

  2. 2.

    Knowles, T. P. J., Vendruscolo, M. & Dobson, C. M. The amyloid state and its association with protein misfolding diseases. Nat. Rev. Mol. Cell Biol. 15, 384–396 (2014).

    Article  Google Scholar 

  3. 3.

    Doussineau, T. et al. Mass determination of entire amyloid fibrils by using mass spectrometry. Angew. Chem. Int. Ed. 55, 2340–2344 (2016).

    Article  Google Scholar 

  4. 4.

    Knowles, T. P. J. & Mezzenga, R. Amyloid fibrils as building blocks for natural and artificial functional materials. Adv. Mater. 28, 6546–6561 (2016).

    Article  Google Scholar 

  5. 5.

    Aumüller, T. & Fändrich, M. Protein chemistry: catalytic amyloid fibrils. Nat. Chem. 6, 273–274 (2014).

    Article  Google Scholar 

  6. 6.

    Altamura, L. et al. A synthetic redox biofilm made from metalloprotein–prion domain chimera nanowires. Nat. Chem. 9, 157–163 (2017).

    Article  Google Scholar 

  7. 7.

    Kovacs, G. G. Molecular pathological classification of neurodegenerative diseases: turning towards precision medicine. Int. J. Mol. Sci. 17, 189 (2016).

    Article  Google Scholar 

  8. 8.

    Jucker, M. & Walker, L. C. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature 501, 45–51 (2013).

    ADS  Article  Google Scholar 

  9. 9.

    Sipe, J. D. et al. Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines. Amyloid 23, 209–213 (2016).

    Article  Google Scholar 

  10. 10.

    Knowles, T. P. J. et al. An analytical solution to the kinetics of breakable filament assembly. Science 326, 1533–1537 (2009).

    ADS  Article  Google Scholar 

  11. 11.

    Glabe, C. G. Common mechanisms of amyloid oligomer pathogenesis in degenerative disease. Neurobiol. Aging 27, 570–575 (2006).

    Article  Google Scholar 

  12. 12.

    Cummings, J. L., Doody, R. & Clark, C. Disease-modifying therapies for Alzheimer disease: challenges to early intervention. Neurology 69, 1622–1634 (2007).

    Article  Google Scholar 

  13. 13.

    Stower, H. Searching for Alzheimer’s disease therapies. Nat. Med. 24, 894–897 (2018).

    Article  Google Scholar 

  14. 14.

    Mercato, L. L. del et al. Charge transport and intrinsic fluorescence in amyloid-like fibrils. Proc. Natl Acad. Sci. USA 104, 18019–18024 (2007).

    ADS  Article  Google Scholar 

  15. 15.

    Tcherkasskaya, O. Photo-activity induced by amyloidogenesis. Protein Sci. 16, 561–571 (2007).

    Article  Google Scholar 

  16. 16.

    Chan, F. T. S. et al. Protein amyloids develop an intrinsic fluorescence signature during aggregation. Analyst 138, 2156–2162 (2013).

    ADS  Article  Google Scholar 

  17. 17.

    Pinotsi, D., Buell, A. K., Dobson, C. M., Schierle, G. S. K. & Kaminski, C. F. A label-free, quantitative assay of amyloid fibril growth based on intrinsic fluorescence. ChemBioChem 14, 846–850 (2013).

    Article  Google Scholar 

  18. 18.

    Handelman, A., Beker, P., Amdursky, N. & Rosenman, G. Physics and engineering of peptide supramolecular nanostructures. Phys. Chem. Chem. Phys. 14, 6391–6408 (2012).

    Article  Google Scholar 

  19. 19.

    Shukla, A. et al. A novel UV laser-induced visible blue radiation from protein crystals and aggregates: scattering artifacts or fluorescence transitions of peptide electrons delocalized through hydrogen bonding? Arch. Biochem. Biophys. 428, 144–153 (2004).

    Article  Google Scholar 

  20. 20.

    Zipfel, W. R. et al. Live tissue intrinsic emission microscopy using multiphoton-excited native fluorescence and second harmonic generation. Proc. Natl Acad. Sci. USA 100, 7075–7080 (2003).

    ADS  Article  Google Scholar 

  21. 21.

    Shaham-Niv, S. et al. Intrinsic fluorescence of metabolite amyloids allows label-free monitoring of their formation and dynamics in live cells. Angew. Chem. Int. Ed. 57, 12444–12447 (2018).

    Article  Google Scholar 

  22. 22.

    Kuo, Y.-M. et al. Comparative analysis of amyloid-β chemical structure and amyloid plaque morphology of transgenic mouse and Alzheimer’s disease brains. J. Biol. Chem. 276, 12991–12998 (2001).

    Article  Google Scholar 

  23. 23.

    Matsuoka, Y. et al. Inflammatory responses to amyloidosis in a transgenic mouse model of Alzheimer’s disease. Am. J. Pathol. 158, 1345–1354 (2001).

    Article  Google Scholar 

  24. 24.

    Marmorstein, A. D., Marmorstein, L. Y., Sakaguchi, H. & Hollyfield, J. G. Spectral profiling of autofluorescence associated with lipofuscin, Bruch’s Membrane, and sub-RPE deposits in normal and AMD eyes. Invest. Ophthalmol. Vis. Sci. 43, 2435–2441 (2002).

    Google Scholar 

  25. 25.

    Haralampus-Grynaviski, N. M. et al. Spectroscopic and morphological studies of human retinal lipofuscin granules. Proc. Natl Acad. Sci. USA 100, 3179–3184 (2003).

    ADS  Article  Google Scholar 

  26. 26.

    Youssef, S. A. et al. Pathology of the aging brain in domestic and laboratory animals, and animal models of human neurodegenerative diseases. Vet. Pathol. 53, 327–348 (2016).

    Article  Google Scholar 

  27. 27.

    Gilissen, E. P. et al. A neuronal aging pattern unique to humans and common chimpanzees. Brain Struct. Funct. 221, 647–664 (2016).

    Article  Google Scholar 

  28. 28.

    Dowson, J. H., Mountjoy, C. Q., Cairns, M. R., Wilton-Cox, H. & Bondareff, W. Lipopigment changes in Purkinje cells in Alzheimer’s disease. J. Alzheimer’s Dis. 1, 71–79 (1998).

    Article  Google Scholar 

  29. 29.

    D’Andrea, M. R. et al. Lipofuscin and Aβ42 exhibit distinct distribution patterns in normal and Alzheimer’s disease brains. Neurosci. Lett. 323, 45–49 (2002).

    Article  Google Scholar 

  30. 30.

    Niyangoda, C., Miti, T., Breydo, L., Uversky, V. & Muschol, M. Carbonyl-based blue autofluorescence of proteins and amino acids. PLoS ONE 12, e0176983 (2017).

    Article  Google Scholar 

  31. 31.

    Tao, K. et al. Quantum confined peptide assemblies with tunable visible to near-infrared spectral range. Nat. Commun. 9, 3217 (2018).

    ADS  Article  Google Scholar 

  32. 32.

    Pinotsi, D. et al. Proton transfer and structure-specific fluorescence in hydrogen bond-rich protein structures. J. Am. Chem. Soc. 138, 3046–3057 (2016).

    Article  Google Scholar 

  33. 33.

    Tomalia, D. A. et al. Non-traditional intrinsic luminescence: inexplicable blue fluorescence observed for dendrimers, macromolecules and small molecular structures lacking traditional/conventional luminophores. Prog. Polym. Sci. 90, 35–117 (2019).

    Article  Google Scholar 

  34. 34.

    Plascencia-Villa, G. et al. High-resolution analytical imaging and electron holography of magnetite particles in amyloid cores of Alzheimer’s disease. Sci. Rep. 6, 24873 (2016).

    ADS  Article  Google Scholar 

  35. 35.

    Meyer, E. P., Ulmann-Schuler, A., Staufenbiel, M. & Krucker, T. Altered morphology and 3D architecture of brain vasculature in a mouse model for Alzheimer’s disease. Proc. Natl Acad. Sci. USA 105, 3587–3592 (2008).

    ADS  Article  Google Scholar 

  36. 36.

    Michael, R. et al. Hyperspectral Raman imaging of neuritic plaques and neurofibrillary tangles in brain tissue from Alzheimer’s disease patients. Sci. Rep. 7, 15603 (2017).

    ADS  Article  Google Scholar 

  37. 37.

    Flynn, J. D., Jiang, Z. & Lee, J. C. Segmental 13C-labeling and Raman microspectroscopy of α-synuclein amyloid formation. Angew. Chem. Int. Ed. 130, 17315–17318 (2018).

    Article  Google Scholar 

  38. 38.

    Xue, C., Lin, T. Y., Chang, D. & Guo, Z. Thioflavin T as an amyloid dye: fibril quantification, optimal concentration and effect on aggregation. R. Soc. Open Sci. 4, 160696 (2017).

    ADS  Article  Google Scholar 

  39. 39.

    Hong, G. et al. Through-skull fluorescence imaging of the brain in a new near-infrared window. Nat. Photon. 8, 723–730 (2014).

    ADS  Article  Google Scholar 

  40. 40.

    Hilderbrand, S. A. & Weissleder, R. Near-infrared fluorescence: application to in vivo molecular imaging. Curr. Opin. Chem. Biol. 14, 71–79 (2010).

    Article  Google Scholar 

  41. 41.

    Bouteiller, C. et al. Novel water-soluble near-infrared cyanine dyes: synthesis, spectral properties, and use in the preparation of internally quenched fluorescent probes. Bioconj. Chem. 18, 1303–1317 (2007).

    Article  Google Scholar 

  42. 42.

    Koeing, A. et al. In vivo mice lung tumor follow-up with fluorescence diffuse optical tomography. J. Biomed. Opt. 13, 011008 (2008).

    ADS  Article  Google Scholar 

  43. 43.

    Koenig, A. et al. Fluorescence diffuse optical tomography for free-space and multifluorophore studies. J. Biomed. Opt. 15, 016016 (2010).

    ADS  Article  Google Scholar 

  44. 44.

    Josserand, V. et al. Electrochemotherapy guided by intraoperative fluorescence imaging for the treatment of inoperable peritoneal micro-metastases. J. Control. Rel. 233, 81–87 (2016).

    Article  Google Scholar 

  45. 45.

    Saar, B. G. et al. Video-rate molecular imaging in vivo with stimulated Raman scattering. Science 330, 1368–1370 (2010).

    ADS  Article  Google Scholar 

  46. 46.

    Camp, C. H. Jr et al. High-speed coherent Raman fingerprint imaging of biological tissues. Nat. Photon. 8, 627–634 (2014).

    ADS  Article  Google Scholar 

  47. 47.

    Hanczyc, P., Samoc, M. & Norden, B. Multiphoton absorption in amyloid protein fibres. Nat. Photon. 7, 969–972 (2013).

    ADS  Article  Google Scholar 

  48. 48.

    Tao, K., Makam, P., Aizen, R. & Gazit, E. Self-assembling peptide semiconductors. Science 358, eaam9756 (2017).

    Article  Google Scholar 

  49. 49.

    Berger, O. et al. Light-emitting self-assembled peptide nucleic acids exhibit both stacking interactions and Watson–Crick base pairing. Nat. Nanotechnol. 10, 353–360 (2015).

    ADS  Article  Google Scholar 

  50. 50.

    Plissonneau, M. et al. Gd-nanoparticles functionalization with specific peptides for ß-amyloid plaques targeting. J. Nanobiotechnol. 14, 60 (2016).

    Article  Google Scholar 

  51. 51.

    Pansieri, J. et al. Mass and charge distributions of amyloid fibers involved in neurodegenerative diseases: mapping heterogeneity and polymorphism. Chem. Sci. 9, 2791–2796 (2018).

    Article  Google Scholar 

  52. 52.

    Sulatskaya, A. I., Rodina, N. P., Povarova, O. I., Kuznetsova, I. M. & Turoverov, K. K. Different conditions of fibrillogenesis cause polymorphism of lysozyme amyloid fibrils. J. Mol. Struct. 1140, 52–58 (2017).

    ADS  Article  Google Scholar 

  53. 53.

    Kavanagh, G. M., Clark, A. H. & Ross-Murphy, S. B. Heat-induced gelation of globular proteins: part 3. molecular studies on low pH β-lactoglobulin gels. Int. J. Biol. Macromol. 28, 41–50 (2000).

    Article  Google Scholar 

  54. 54.

    Lembré, P., Martino, P. D. & Vendrely, C. Amyloid peptides derived from CsgA and FapC modify the viscoelastic properties of biofilm model matrices. Biofouling 30, 415–426 (2014).

    Article  Google Scholar 

  55. 55.

    Peng, H., Ruan, Z., Long, F., Simpson, J. H. & Myers, E. W. V3D enables real-time 3D visualization and quantitative analysis of large-scale biological image data sets. Nat. Biotechnol. 28, 348–353 (2010).

    Article  Google Scholar 

  56. 56.

    Peng, H., Bria, A., Zhou, Z., Iannello, G. & Long, F. Extensible visualization and analysis for multidimensional images using Vaa3D. Nat. Protoc. 9, 193–208 (2014).

    Article  Google Scholar 

  57. 57.

    Peng, H. et al. Virtual finger boosts three-dimensional imaging and microsurgery as well as terabyte volume image visualization and analysis. Nat. Commun. 5, 4342 (2014).

    ADS  Article  Google Scholar 

Download references

Acknowledgements

This work was supported by Euronanomed ENMII JTC2012 (project 2011-ERA-002-01- Dia-Amyl) and the French National Research Agency (ANR) through the grants ANR-12-RPIB Multimage and ANR-17-CE09-0013 Bionics (ANR-17-CE09-0013-01 and ANR-17-CE09-0013-02). J.P. is grateful to the Fondation pour la Recherche Médicale (FRM) for granting his PhD fellowship (grant number FRM DBS2013112844<0). A.R. and S.-J.L. acknowledge Commissariat à l’Energie Atomique et aux Energies Alternatives (CEA) for the funding of their respective CEA-Phare PhD fellowships. We thank M. Dumoulin for the gift of α-synuclein, and S. Denti and S. Chierici for the gift of hTau used in this work. This research benefited from resources of the European Synchrotron Radiation Facility (ESRF, Grenoble, France). In particular, we acknowledge M. Burghammer, M. Sztucki and T.G. Dane of the Microfocus beamline ID13. We thank D. Fenel, C. Moriscot and G. Schoehn from the Electron Microscopy platform of the Integrated Structural Biology of Grenoble (ISBG, UMI3265). We thank L. Gonon and V. Mareau for helpful discussions on Raman scattering. We are grateful to L. Kurzawa (µLife platform of CEA-Grenoble/BIG) for helpful discussions and specific advice on confocal microscopy. Fluorescence imaging systems used in this study were acquired thanks to France Life Imaging (French program “Investissement d’Avenir” grant; “Infrastructure d’avenir en Biologie Sante”, ANR-11-INBS-44 0006). This work was also supported by NeuroCoG IDEX UGA in the framework of the “Investissements d’avenir” programme (ANR-15-IDEX-02).

Author information

Affiliations

Authors

Contributions

J.P. and V.F. conceived and designed the work, and wrote most of the paper. J.P., S-J.L., D.I., O.C.-P. and C.V. performed the in vitro characterizations of the amyloid fibres. A.R., T.D. and P.R. conceived, performed and analysed the X-ray scattering experiments. M.M.S. and E.K. collected and prepared the human samples. J.P. and C.M. designed and performed the ex vivo experiments. V.J., M.G., J.V., A.F., Y.U. and J.L.C. performed the 3D and 2D fluorescence imaging and analysed the data. J.P., C.M. and V.F. coordinated all experiments and compiled the results. J.P., C.M., P.R. and V.F. edited the text. All co-authors discussed and commented on the manuscript.

Corresponding author

Correspondence to Vincent Forge.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

This file contains more information about the work and Supplementary Figures 1–14.

Reporting Summary

Supplementary Video 1

Video made with 60 ex vivo confocal microscopy images of isolated amyloid plaque in brain tissue from a patient with Alzheimer’s disease within the hippocampus area.

Supplementary Video 2

Video made with 60 ex vivo confocal microscopy images of amyloid deposits near a blood vessel in brain tissue from a patient with Alzheimer’s disease within the hippocampus area.

Supplementary Video 3

Sequential 3D modelling using ex vivo confocal microscopy images of isolated amyloid plaque in brain tissue from a patient with Alzheimer’s disease within the hippocampus area.

Supplementary Video 4

Sequential 3D modelling using ex vivo confocal microscopy images of amyloid deposits near a blood vessel in brain tissue from a patient with Alzheimer’s disease within the hippocampus area.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Pansieri, J., Josserand, V., Lee, SJ. et al. Ultraviolet–visible–near-infrared optical properties of amyloid fibrils shed light on amyloidogenesis. Nat. Photonics 13, 473–479 (2019). https://doi.org/10.1038/s41566-019-0422-6

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing