Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Sep 30;27(19):6448.
doi: 10.3390/molecules27196448.

Applications of Single-Molecule Vibrational Spectroscopic Techniques for the Structural Investigation of Amyloid Oligomers

Katrin Ha Phuong Vu  1   2   3 , Gerhard Heinrich Blankenburg  1   3   4 , Leonardo Lesser-Rojas  5   6 , Chia-Fu Chou  3   7
Affiliations
Review

Applications of Single-Molecule Vibrational Spectroscopic Techniques for the Structural Investigation of Amyloid Oligomers

Katrin Ha Phuong Vu et al. Molecules. .

Abstract

Amyloid oligomeric species, formed during misfolding processes, are believed to play a major role in neurodegenerative and metabolic diseases. Deepening the knowledge about the structure of amyloid intermediates and their aggregation pathways is essential in understanding the underlying mechanisms of misfolding and cytotoxicity. However, structural investigations are challenging due to the low abundance and heterogeneity of those metastable intermediate species. Single-molecule techniques have the potential to overcome these difficulties. This review aims to report some of the recent advances and applications of vibrational spectroscopic techniques for the structural analysis of amyloid oligomers, with special focus on single-molecule studies.

Keywords: amyloid intermediates; amyloid oligomers; protein structure; single molecule; vibrational spectroscopy.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic illustration of amyloid aggregation. (a) On-pathway mechanism: native monomers misfold and undergo conformational change to form prefibrillar oligomers, protofibrils, and mature fibrils. (b) Alternative pathway induced by metal ions: monomers form off-pathway oligomers which do not end up as fibrils but amorphous aggregates. (c) Schematic illustration of parallel and anti-parallel cross-β structure. Amyloid fibrils have parallel cross-β conformation.
Figure 2
Figure 2
(a) Schematic overview of the immuno-infrared-sensor. If the marker band (amide I) is dominated by disordered or α-helical monomeric isoforms, the patient is diagnosed as non-AD (blue). If β-sheet isoforms are enriched (red), the amide I signal is shifted below the threshold (1642 cm−1), indicating AD. Part of figure reproduced from Ref. [64] with permission. (b) Two-dimensional IR spectra of Aβ42 aggregated for 30 min, 1 day, and 7 days (representative for the transition from oligomers to mature fibrils); diagonal slices through the fundamental transition (dashed line); and representative TEM images for Aβ42. The 1610 cm−1 transition is marked with an asterisk in the 2D spectra and diagonal cuts. Part of figure adapted with permission from Ref. [65]. Copyright 2018 American Chemical Society.
Figure 3
Figure 3
(a) Picture of the silver-spotted substrate used for SERS analysis showing a drop of Aβ42 solution deposited on a 2 mm large spot. Inset: contact angle image of a water droplet after deposition on the spot; exemplary AFM image of the spot showing intertwined AgNWs. (b) Series of SERS spectra of Ab42 oligomers over 2 h, 24 h, 48 h, and 96 h incubation time and of mature fibrils (from bottom to top). (c) SERS spectrum of ADDLs compared to that of type A+ (toxic) and A- (non-toxic) oligomers. SERS spectra of polyHis, polyGlu, polyArg, and polyLys are also displayed for comparison. Bands of polyLys and/or polyArg describing relevant spectral features of type A+ oligomers and ADDLs are identified with colored boxes. Figure adapted from Ref. [82] with permission.
Figure 4
Figure 4
(a) AFM maps of Aβ42 oligomers with corresponding IR spectra. Part of figure reproduced from Ref. [88] with permission. (b) Schematic illustration of an AFM-IR setup (above). AFM maps of amyloid fibrils and oligomers with corresponding IR spectra (below). Part of figure reproduced from Ref. [89] with permission. Copyright 2020 Feuillie et al. (c) AFM maps and corresponding IR line absorption maps of various oligomeric aggregates. Part of figure adapted with permission from Ref. [90]. Copyright 2021 American Chemical Society.
Figure 5
Figure 5
(a) TERS spectra of toxic and non-toxic oligomer samples. Part of figure reproduced from Ref. [111] with permission. Copyright 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (b) Above: Cartoon of the working principle of the nanogap device. Peptides are trapped via DEP inside the gap between a pair of electrodes and the SERS signal is simultaneously measured (upper inset); TEM images of Aβ40 aggregates with and without the presence of Zn2+ (lower insets); below: SERS spectra of Aβ40 in solution trapped with the nanogap device with and without Zn2+ after different incubation times. Figure adapted with permission from Ref. [112]. Copyright 2021 American Chemical Society.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Chiti F., Dobson C.M. Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade. Annu. Rev. Biochem. 2017;86:27–68. doi: 10.1146/annurev-biochem-061516-045115. - DOI - PubMed
    1. Sengupta U., Nilson A.N., Kayed R. The Role of Amyloid-beta Oligomers in Toxicity, Propagation, and Immunotherapy. EBioMedicine. 2016;6:42–49. doi: 10.1016/j.ebiom.2016.03.035. - DOI - PMC - PubMed
    1. Bucciantini M., Giannoni E., Chiti F., Baroni F., Formigli L., Zurdo J., Taddei N., Ramponi G., Dobson C.M., Stefani M. Inherent toxicity of aggregates implies a common mechanism for protein misfolding diseases. Nature. 2002;416:507–511. doi: 10.1038/416507a. - DOI - PubMed
    1. Kayed R., Head E., Thompson J.L., McIntire T.M., Milton S.C., Cotman C.W., Glabe C.G. Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science. 2003;300:486–489. doi: 10.1126/science.1079469. - DOI - PubMed
    1. Selkoe D.J. Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behav. Brain. Res. 2008;192:106–113. doi: 10.1016/j.bbr.2008.02.016. - DOI - PMC - PubMed