title: Mechanisms for the Insertion of Toxic, Fibril-like β-Amyloid Oligomers into the Membrane.
abstract: Amyloid-β (Aβ) oligomers destabilize cellular ionic homeostasis, mediating Alzheimer's disease (AD). It is still unclear whether the mechanism (i) is mediated by cell surface receptors; (ii) is direct, with Aβ oligomers interacting with membrane lipids; or (iii) both mechanisms take place. Recent studies indicate that Aβ oligomers may act by either of the last two. Little is known about the oligomers' structures and how they spontaneously insert into the membrane. Using explicit solvent molecular dynamics (MD) simulations, we show that fibril-like Aβ(17-42) (p3) oligomer is capable of penetrating the membrane. Insertion is similar to that observed for protegrin-1 (PG-1), a cytolytic β-sheet-rich antimicrobial peptide (AMP). Both Aβ and PG-1 favor the amphipathic interface of the lipid bilayer in the early stage of interaction with the membrane. U-shaped Aβ oligomers are observed in solution and in the membrane, suggesting that the preformed seeds can be shared by amyloid fibrils in the growth phase and membrane toxicity. Here we provide sequential events in possible Aβ oligomer membrane-insertion pathways. We speculate that for the U-shaped motif, a trimer is the minimal oligomer size to insert effectively. We propose that monomers and dimers may insert in (apparently on-pathway) aggregation-intermediate β-hairpin state, and may (or may not) convert to a U-shape in the bilayer. Together with earlier observations, our results point to a non-specific, broadly heterogeneous landscape of membrane-inserting oligomer conformations, pathways, and membrane-mediated toxicity of β-rich oligomers.
authors: Basic Science Program, SAIC-Frederick, Inc., Center for Cancer Research Nanobiology Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA.
authors: Hyunbum
authors: H
authors: Jang
authors: Laura
authors: L
authors: Connelly
authors: Fernando Teran
authors: FT
authors: Arce
authors: Srinivasan
authors: S
authors: Ramachandran
authors: Bruce L
authors: BL
authors: Kagan
authors: Ratnesh
authors: R
authors: Lal
authors: Ruth
authors: R
authors: Nussinov