Structure specific amyloid precipitation in biofluids
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Klenerman, D. Structure specific amyloid precipitation in biofluids. Nature Chemistry https://doi.org/10.17863/CAM.84704
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 (AP). We use a structure-specific chemical dimer; a Y shaped, bioinspired small molecule with two capture groups for AP 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 characterise 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.
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).
Royal Society (RP150066)
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This record's DOI: https://doi.org/10.17863/CAM.84704
This record's URL: https://www.repository.cam.ac.uk/handle/1810/337289
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