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Stabilization of native amyloid ß-protein oligomers by Copper and Hydrogen peroxide Induced Cross-linking of Unmodified Proteins (CHICUP)

journal contribution
posted on 2023-06-09, 00:12 authored by Thomas L Williams, Louise SerpellLouise Serpell, Brigita Urbanc
Oligomeric assemblies are postulated to be proximate neurotoxic species in human diseases associated with aberrant protein aggregation. Their heterogeneous and transient nature makes their structural characterization difficult. Size distributions of oligomers of several amyloidogenic proteins, including amyloid ß-protein (Aß) relevant to Alzheimer's disease (AD), have been previously characterized in vitro by photo-induced cross-linking of unmodified proteins (PICUP) followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Due to non-physiological conditions associated with the PICUP chemistry, Aß oligomers cross-linked by PICUP may not be representative of in vivo conditions. Here, we examine an alternative Copper and Hydrogen peroxide Induced Cross-linking of Unmodified Proteins (CHICUP), which utilizes naturally occurring divalent copper ions and hydrogen peroxide and does not require photo activation. Our results demonstrate that CHICUP and PICUP applied to the two predominant Aß alloforms, Aß40 and Aß42, result in similar oligomer size distributions. Thioflavin T fluorescence data and atomic force microscopy images demonstrate that both CHICUP and PICUP stabilize Aß oligomers and attenuate fibril formation. Relative to noncross-linked peptides, CHICUP-treated Aß40 and Aß42 cause prolonged disruption to biomimetic lipid vesicles. CHICUP-stabilized Aß oligomers link the amyloid cascade, metal, and oxidative stress hypotheses of AD into a more comprehensive understanding of the molecular basis of AD pathology. Because copper and hydrogen peroxide are elevated in the AD brain, CHICUP-stabilized Aß oligomers are biologically relevant and should be further explored as a new therapeutic target.

History

Publication status

  • Published

File Version

  • Published version

Journal

BBA - Proteins and Proteomics

ISSN

1570-9639

Publisher

Elsevier

Issue

3

Volume

1864

Page range

249-259

Department affiliated with

  • Biochemistry Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2016-02-05

First Compliant Deposit (FCD) Date

2016-02-04

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