Molecular Insights for Alzheimer's Disease: An Unexplored Storyline on the Nanoscale Impact of Nascent Aβ 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 (Aβ) peptide interactions with supported lipid bilayers (SLBs). The MD simulations showed that nascent Aβ 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 Aβ monomers and oligomers when interacting with SLBs. When Aβ 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 Aβ and the SLBs were detected when SLBs free of Aβ were exposed to Aβ. This study suggests that Aβ can remain in the membrane after cleavage by γ-secretase and cause severe damage to the membrane.