A Common Pathway for Detergent-Assisted Oligomerization of Aβ42

Amyloid beta (A{beta}) aggregation is a slow process without seeding or assisted nucleation. Sodium dodecyl sulfate (SDS) micelles stabilize A{beta}42 small oligomers (in the dimer-tetramer range); subsequent SDS removal leads to a 150-kD A{beta}42 oligomer. Dodecylphosphorylcholine (DPC) micelles also stabilize an A{beta}42 tetramer. Here we characterize the detergent-assisted oligomerization pathway by solid-state NMR spectroscopy and molecular dynamics simulations. SDS and DPC-induced oligomers have the same structure, implying a common oligomerization pathway. An antiparallel {beta}-sheet formed by the C-terminal region, the only stable structure in SDS and DPC micelles, is directly incorporated into the 150-kD oligomer. Three Gly residues (at positions 33, 37, and 38) create holes that are filled by the SDS and DPC hydrocarbon tails, thereby turning a potentially destabilizing feature into a stabilizing factor. These observations have implications for endogenous A{beta} aggregation at cellular interfaces.