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Rationally Designed Antibodies as Research Tools to Study the Structure–Toxicity Relationship of Amyloid-β Oligomers

Published version
Peer-reviewed

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Authors

Limbocker, Ryan 
Mannini, Benedetta 
Cataldi, Rodrigo 
Chhangur, Shianne 
Wright, Aidan K. 

Abstract

Alzheimer’s disease is associated with the aggregation of the amyloid-β peptide (Aβ), resulting in the deposition of amyloid plaques in brain tissue. Recent scrutiny of the mechanisms by which Aβ aggregates induce neuronal dysfunction has highlighted the importance of the Aβ oligomers of this protein fragment. Because of the transient and heterogeneous nature of these oligomers, however, it has been challenging to investigate the detailed mechanisms by which these species exert cytotoxicity. To address this problem, we demonstrate here the use of rationally designed single-domain antibodies (DesAbs) to characterize the structure−toxicity relationship of Aβ oligomers. For this purpose, we use Zn2+-stabilized oligomers of the 40-residue form of Aβ (Aβ40) as models of brain Aβ oligomers and two single-domain antibodies (DesAb18-24 and DesAb34-40), designed to bind to epitopes at residues 18−24 and 34−40 of Aβ40, respectively. We found that the DesAbs induce a change in structure of the Zn2+-stabilized Aβ40 oligomers, generating a simultaneous increase in their size and solvent-exposed hydrophobicity. We then observed that these increments in both the size and hydrophobicity of the oligomers neutralize each other in terms of their effects on cytotoxicity, as predicted by a recently proposed general structure−toxicity relationship, and observed experimentally. These results illustrate the use of the DesAbs as research tools to investigate the biophysical and cytotoxicity properties of Aβ oligomers.

Description

Keywords

protein misfolded oligomers, structure–toxicity relationship, rationally designed antibodies, research tools, biophysics, amyloid-β, Alzheimer’s disease

Journal Title

International Journal of Molecular Sciences

Conference Name

Journal ISSN

1422-0067

Volume Title

21

Publisher

MDPI