Molecular Insights for Alzheimer’s Disease: An Unexplored Storyline on the Nanoscale Impact of Nascent Aβ_1–42 toward the Lipid Membrane

Deciphering the mechanism of Alzheimer's disease is a key element for designing an efficient therapeutic strategy. Molecular dynamics (MD) calculations, atomic force microscopy, and infrared spectroscopy were combined to investigate β-amyloid (Aβ1-42) peptide interactions with supported lipid bilayers (SLBs). The MD simulations showed that nascent Aβ1-42 monomers remain anchored within a model phospholipid bilayer's hydrophobic core, which suggests their stability in their native environment. We tested this prediction experimentally by studying the behavior of Aβ1-42 monomers and oligomers when interacting with SLBs. When Aβ1-42 monomers and oligomers were self-assembled with a lipid bilayer and deposited as an SLB, they remain within the bilayers. Their presence in the bilayers induces destabilization of the model membranes. No specific interactions between Aβ1-42 and the SLBs were detected when SLBs free of Aβ1-42 were exposed to Aβ1-42. This study suggests that Aβ can remain in the membrane after cleavage by γ-secretase and cause severe damage to the membrane.