Stabilization of small Aβ oligomers in SDS micelles.

Abstract

Aβ fibrillation is a slow process without seeding or assisted nucleation. It was observed previously that SDS micelles promote Aβ40 fibrillation and stabilize Aβ42 small oligomers (in the dimer to tetramer range). Here we characterized small oligomers in SDS micelles by molecular dynamics simulations and solid-state NMR spectroscopy. Parallel β-sheets formed by the C-terminal region (Ala30 to the C-terminus, or C-strand) of Aβ40 and Aβ42 tetramers are unstable in SDS micelles, due to fraying starting at Gly37 and Gly38. In contrast, an antiparallel β-sheet formed by four Aβ42 C-strands is stable, with the tails of SDS molecules inserted next to the β-sheet in the voids above Gly33 of one strand and Gly37 and Gly38 one of the next strand. This deep insertion allows the SDS tails to form hydrophobic interactions with numerous nearby nonpolar sidechains. Measurements of intermolecular 13C-13C dipolar couplings show that the SDS-stabilized antiparallel tetramer is an on-pathway intermediate for a 150-kD oligomer formed on dialysis. These observations have implications for the stimulation of endogenous Aβ aggregation at cellular interfaces.