Dimers of the amyloid β-protein (Aβ) are believed to play an important role in Alzheimer's disease. In the absence of sufficient brain-derived dimer we studied one of the only possible dimers that could be produced in vivo, dityrosine cross-linked Aβ, [Aβ]DiY. For comparison we used Aβ monomer and a design dimer cross-linked by substitution of serine 26 with cystine, [AβS26C]2. We show that like monomer, unaggregated dimers, lack appreciable structure and fail to alter LTP. Importantly, dimers exhibit subtly different structural propensities from monomer and each other, and can self-associate to form larger assemblies. Although [Aβ]DiY and [AβS26C]2 have distinct aggregation pathways they both populate bioactive soluble assemblies for longer durations than Aβ monomer. Our results indicate that the link between Aβ dimers and Alzheimer's disease results from the ability of dimers to further assemble and form synaptotoxic assemblies that persist for long periods of time.
