Journal
NATURE CHEMISTRY
Volume 14, Issue 9, Pages 1045-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41557-022-00976-3
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Funding
- National Institute of Health Research University College London Hospitals Biomedical Research Centre
- MRC [MR/T008199/1]
- Swedish Research Council [2018-02532]
- European Research Council [681712, 669237, 804581]
- Swedish State Support for Clinical Research [ALFGBG-720931]
- UK Dementia Research Institute at University College London (UCL)
- Royal Society
- UK Dementia Research Institute at Cambridge
- Royal Society for the University Research Fellowship [UF120277]
- National Institutes of Health [R01GM121573]
- Michael J. Fox Grant [10200]
- European Research Council (ERC) [804581] Funding Source: European Research Council (ERC)
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This study presents a method called "amyloid precipitation" to capture amyloid-containing aggregates in human biofluids in an unbiased way. By using a specific structure-specific chemical dimer, the researchers were able to target the amyloid structure of all protein aggregates present in human cerebrospinal fluid, isolate them for analysis, and characterize them using single-molecule fluorescence imaging and mass spectrometry.
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 beta-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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