Alzheimer Aβ peptide interactions with lipid membranes

Abstract

F ibrillar aggregates of misfolded amy-loid proteins are involved in a variety of diseases such as Alzheimer disease (AD), type 2 diabetes, Parkinson, Huntington and prion-related diseases. In the case of AD amyloid β (Aβ) pep-tides, the toxicity of amyloid oligo-mers and larger fibrillar aggregates is related to perturbing the biological function of the adjacent cellular mem-brane. We used atomistic molecular dynamics (MD) simulations of Aβ 9–40 fibrillar oligomers modeled as protofila-ment segments, including lipid bilayers and explicit water molecules, to probe the first steps in the mechanism of Aβ-membrane interactions. Our study identifies the electrostatic interaction between charged peptide residues and the lipid headgroups as the principal driving force that can modulate the further penetration of the C-termini of amyloid fibrils or fibrillar oligomers into the hydrophobic region of lipid membranes. These findings advance our understanding of the detailed molecular mechanisms and the effects related to Aβ-membrane interactions, and suggest a polymorphic structural character of amyloid ion channels embedded in lipid bilayers. While inter-peptide hydro-gen bonds leading to the formation of β-strands may still play a stabilizing role in amyloid channel structures, these may also present a significant helical content in peptide regions (e.g., termini) that are subject to direct interactions with lipids rather than with neighbor-ing Aβ peptides.