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

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by deposition of extracellular amyloid plaques comprised from fibrillar aggregates of the amyloid-beta peptide (A beta). Cu2+ interactions with A beta appear to be involved in both the production of reactive oxygen species and the misfolding of A beta into oligomeric intermediates including covalently cross-linked dimers. We have previously investigated the Cu2+ coordination of A beta monomers in detail, whilst others have shown that A beta fibrils coordinate Cu2+ in a similar manner to A beta monomers. However, the coordination of low-molecular-weight A beta 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 A beta 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 A beta monomers and fibrils, which may be relevant to the greater toxicity of low-molecular-weight A beta oligomers in AD.