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

Substantial evidence suggests that soluble oligomers of A beta 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 A beta and dityrosine cross-linked A beta dimers have been proposed as the physiologically relevant A beta species linked to the progression of AD. We describe the synthesis and characterization of dityrosine-linked A beta dimers and demonstrate that, in contrast to other covalently linked A beta dimers, dityrosine-linked A beta dimers form discrete, stable, soluble aggregates. Furthermore, dityrosine-linked A beta dimers display increased toxicity in a neuronal cell-line assay compared with the corresponding monomer, consistent with the hypothesis that dityrosine-linked A beta dimers are implicated in the progression of AD.