Structure-specific amyloid precipitation in biofluids.
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Authors
Brinkmalm, A
Pearson, CM
Kulenkampff, K
Emin, D
Lee, JE
Carr, AR
Zetterberg, H
Publication Date
2022-09Journal Title
Nat Chem
ISSN
1755-4330
Publisher
Springer Science and Business Media LLC
Type
Article
This Version
AM
Metadata
Show full item recordCitation
Rodrigues, M., Bhattacharjee, P., Brinkmalm, A., Do, D., Pearson, C., De, S., Ponjavic, A., et al. (2022). Structure-specific amyloid precipitation in biofluids.. Nat Chem https://doi.org/10.1038/s41557-022-00976-3
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.
Keywords
Amyloid, Amyloid beta-Peptides, Bodily Secretions, Humans, Protein Aggregates
Sponsorship
HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931) and the UK Dementia Research Institute at UCL. DK is supported by grants from the European Research Council (#669237), the Royal Society and UK Dementia Research Institute at Cambridge. We thank the Royal Society for the University Research Fellowship to SFL (UF120277), TNS: National Institutes of Health (R01GM121573). Also, Michael J. Fox Grant to SFL and TNS (grant ID: 10200). JAV is supported by the European Research Council with an ERC Starting Grant (804581).
Funder references
Royal Society (RP150066)
European Research Council (669237)
Identifiers
External DOI: https://doi.org/10.1038/s41557-022-00976-3
This record's URL: https://www.repository.cam.ac.uk/handle/1810/337289
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