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Enming Zhang

Research team manager

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A Palette of Fluorescent Aβ42 Peptides Labelled at a Range of Surface-Exposed Sites

Author

  • Dev Thacker
  • Mara Bless
  • Mohammad Barghouth
  • Enming Zhang
  • Sara Linse

Summary, in English

Fluorescence-based single molecule techniques provide important tools towards understanding the molecular mechanism of complex neurodegenerative diseases. This requires efficient covalent attachment of fluorophores. Here we create a series of cysteine mutants (S8C, Y10C, S26C, V40C, and A42C) of Aβ42, involved in Alzheimer’s disease, based on exposed positions in the fibril structure and label them with the Alexa-fluorophores using maleimide chemistry. Direct stochastic optical reconstruction microscopy imaging shows that all the labelled mutants form fibrils that can be detected by virtue of Alexa fluorescence. Aggregation assays and cryo-electron micrographs establish that the careful choice of labelling position minimizes the perturbation of the aggregation process and fibril structure. Peptides labelled at the N-terminal region, S8C and Y10C, form fibrils independently and with wild-type. Peptides labelled at the fibril core surface, S26C, V40C and A42C, form fibrils only in mixture with wild-type peptide. This can be understood on the basis of a recent fibril model, in which S26, V40 and A42 are surface exposed in two out of four monomers per fibril plane. We provide a palette of fluorescently labelled Aβ42 peptides that can be used to gain understanding of the complex mechanisms of Aβ42 self-assembly and help to develop a more targeted approach to cure the disease.

Department/s

  • Biochemistry and Structural Biology
  • NanoLund: Center for Nanoscience
  • MultiPark: Multidisciplinary research focused on Parkinson´s disease
  • Diabetes - Islet Patophysiology
  • EXODIAB: Excellence of Diabetes Research in Sweden

Publishing year

2022-02-01

Language

English

Publication/Series

International Journal of Molecular Sciences

Volume

23

Issue

3

Document type

Journal article

Publisher

MDPI AG

Topic

  • Biochemistry and Molecular Biology
  • Physical Chemistry

Keywords

  • Amyloid formation
  • Imaging
  • Optical spectroscopy

Status

Published

Research group

  • Diabetes - Islet Patophysiology

ISBN/ISSN/Other

  • ISSN: 1661-6596