Structure-specific amyloid precipitation in biofluids

M Rodrigues; P Bhattacharjee; A Brinkmalm; D T Do; C M Pearson; S De; A Ponjavic; J A Varela; K Kulenkampff; I Baudrexel; D Emin; F S Ruggeri; J E Lee; A R Carr; T P J Knowles; H Zetterberg; T N Snaddon; S Gandhi; S F Lee; D Klenerman

doi:10.1038/s41557-022-00976-3

Structure-specific amyloid precipitation in biofluids

Nat Chem. 2022 Sep;14(9):1045-1053. doi: 10.1038/s41557-022-00976-3. Epub 2022 Jul 7.

Authors

M Rodrigues^{1

2}, P Bhattacharjee^{3

4}, A Brinkmalm^{3

4}, D T Do⁵, C M Pearson⁵, S De^{1

2

6}, A Ponjavic^{1

7

8}, J A Varela^{1

9}, K Kulenkampff^{1

2}, I Baudrexel¹, D Emin^{1

2}, F S Ruggeri^{1

10

11}, J E Lee^{1

12}, A R Carr¹, T P J Knowles¹, H Zetterberg^{3

4

13

14}, T N Snaddon¹⁵, S Gandhi^{16

17}, S F Lee¹⁸, D Klenerman^{19

20}

Affiliations

¹ Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK.
² UK Dementia Research Institute, University of Cambridge, Cambridge, UK.
³ Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
⁴ Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden.
⁵ Department of Chemistry, Indiana University, Bloomington, IN, USA.
⁶ Sheffield Institute for Translational Neuroscience, University of Sheffield, Western Bank, Sheffield, UK.
⁷ School of Physics and Astronomy, University of Leeds, Leeds, UK.
⁸ School of Food Science and Nutrition, University of Leeds, Leeds, UK.
⁹ School of Physics and Astronomy, University of St Andrews, St Andrews, UK.
¹⁰ Laboratory of Organic Chemistry, Wageningen University & Research, Wageningen, The Netherlands.
¹¹ Physical Chemistry and Soft Matter, Wageningen University & Research, Wageningen, The Netherlands.
¹² School of Chemistry, University of Edinburgh, Edinburgh, UK.
¹³ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.
¹⁴ UK Dementia Research Institute, UCL, London, UK.
¹⁵ Department of Chemistry, Indiana University, Bloomington, IN, USA. [email protected].
¹⁶ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK. [email protected].
¹⁷ The Francis Crick Institute, London, UK. [email protected].
¹⁸ Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK. [email protected].
¹⁹ Yusuf Hamied Department of Chemistry, University of Cambridge, Cambridge, UK. [email protected].
²⁰ UK Dementia Research Institute, University of Cambridge, Cambridge, UK. [email protected].

PMID: 35798951
DOI: 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amyloid beta-Peptides
Amyloid* / chemistry
Bodily Secretions* / chemistry
Humans
Protein Aggregates* / physiology

Substances

Amyloid
Amyloid beta-Peptides
Protein Aggregates

Abstract

Publication types

MeSH terms

Substances

Grants and funding