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Biochim Biophys Acta. 2016 Mar;1864(3):249-259. doi: 10.1016/j.bbapap.2015.12.001. Epub 2015 Dec 15.

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

Author information

1
Department of Physics, Drexel University, Philadelphia, PA 19104, USA.
2
School of Life Sciences, University of Sussex, Falmer, East Sussex, UK.
3
Department of Physics, Drexel University, Philadelphia, PA 19104, USA; Faculty of Mathematics and Physics, University of Ljubljana, Slovenia. Electronic address: brigita@drexel.edu.

Abstract

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 β-protein (Aβ) 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, Aβ 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 Aβ alloforms, Aβ40 and Aβ42, result in similar oligomer size distributions. Thioflavin T fluorescence data and atomic force microscopy images demonstrate that both CHICUP and PICUP stabilize Aβ oligomers and attenuate fibril formation. Relative to noncross-linked peptides, CHICUP-treated Aβ40 and Aβ42 cause prolonged disruption to biomimetic lipid vesicles. CHICUP-stabilized Aβ 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 Aβ oligomers are biologically relevant and should be further explored as a new therapeutic target.

KEYWORDS:

Alzheimer's disease; Amyloid fibril; Amyloid β-protein; Copper; Hydrogen peroxide; Oligomer

PMID:
26699836
DOI:
10.1016/j.bbapap.2015.12.001
[Indexed for MEDLINE]

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