Synthetic dityrosine-linked β-amyloid dimers form stable, soluble, neurotoxic oligomers

Abstract

Substantial evidence suggests that soluble oligomers of Aβ are the neurotoxic form resulting in progression of Alzheimer's disease (AD). Tyrosine-10 has been identified as a pivotal residue in the neurotoxicity of Aβ and dityrosine cross-linked Aβ dimers have been proposed as the physiologically relevant Aβ species linked to the progression of AD. We describe the synthesis and characterization of dityrosine-linked Aβ dimers and demonstrate that, in contrast to other covalently linked Aβ dimers, dityrosine-linked Aβ dimers form discrete, stable, soluble aggregates. Furthermore, dityrosine-linked Aβ dimers display increased toxicity in a neuronal cell-line assay compared with the corresponding monomer, consistent with the hypothesis that dityrosine-linked Aβ dimers are implicated in the progression of AD.