Molecular Insights for Alzheimer's Disease: An Unexplored Storyline on the Nanoscale Impact of Nascent A beta(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 beta-amyloid (A beta(1-42)) peptide interactions with supported lipid bilayers (SLBs). The MD simulations showed that nascent A beta(1-42) 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 A beta(1-42) monomers and oligomers when interacting with SLBs. When A beta(1-42) monomers and oligomers were selfassembled 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 A beta(1-42) and the SLBs were detected when SLBs free of A beta(1-42) were exposed to A beta(1-42). This study suggests that A beta can remain in the membrane after cleavage by.-secretase and cause severe damage to the membrane.