Cu²⁺ Coordination of Covalently Cross-linked β-Amyloid Dimers

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by deposition of extracellular amyloid plaques comprised from fibrillar aggregates of the amyloid-β peptide (Aβ). Cu²⁺ interactions with Aβ appear to be involved in both the production of reactive oxygen species and the misfolding of Aβ into oligomeric intermediates including covalently cross-linked dimers. We have previously investigated the Cu²⁺ coordination of Aβ monomers in detail, whilst others have shown that Aβ fibrils coordinate Cu²⁺ in a similar manner to Aβ monomers. However, the coordination of low-molecular-weight Aβ species, which are believed to be responsible for neuronal dysfunction in AD, has not been widely investigated. Here, we report the first study of Cu²⁺ coordination by synthetic Aβ dimers containing an artificial diaminopimelic acid (DAP) or a dityrosine cross-link at residue 10. Our preliminary findings show that dityrosine cross-linking imparts unique structural constraints, resulting in Cu²⁺ coordination distinct from Aβ monomers and fibrils, which may be relevant to the greater toxicity of low-molecular-weight Aβ oligomers in AD.