Surprising toxicity and assembly behaviour of amyloid β-protein oxidized to sulfone

A beta (amyloid beta-peptide) is believed to cause AD (Alzheimer's disease). A beta 42 (A beta comprising 42 amino acids) is substantially more neurotoxic than A beta 40 (A beta comprising 40 amino acids), and this increased toxicity correlates with the existence of unique A beta 42 oligomers. Met(35) oxidation to sulfoxide or sulfone eliminates the differences in early oligomerization between A beta 40 and A beta 42. Met(35) oxidation to sulfoxide has been reported to decrease A beta assembly kinetics and neurotoxicity, whereas oxidation to sulfone has rarely been studied. Based on these data, we expected that oxidation of A beta to sulfone would also decrease its toxicity and assembly kinetics. To test this hypothesis, we compared systematically the effect of the wild-type, sulfoxide and sulfone forms of A beta 40 and A beta 42 on neuronal viability, dendritic spine morphology and macroscopic Ca2+ currents in primary neurons, and correlated the data with assembly kinetics. Surprisingly, we found that, in contrast with A beta-sulfoxide, A beta-sulfone was as toxic and aggregated as fast, as wild-type A beta. Thus, although A beta-sulfone is similar to A beta-sulfoxide in its dipole moment and oligomer size distribution, it behaves similarly to wild-type A beta in its aggregation kinetics and neurotoxicity. These surprising data decouple the toxicity of oxidized A beta from its initial oligomerization, and suggest that our current understanding of the effect of methionine oxidation in A beta is limited.