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

Abstract

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.

The Influence of Lipid Electric Charge on the Binding of Aβ(1–42) Amyloid Peptide to Bilayers in the Liquid-Ordered State

“…The former appears to occur preferentially in more ordered domains so that Aβ would be generated in those domains, while deposition/aggregation could well take place, partly or totally, in different membrane regions, e.g., adjacent disordered domains. Note, however, that Siniscalco et al [ 37 ] support the idea that the nascent Aβ polypeptides are immediately bound to the underlying bilayer, in principle, an ordered lipid structure. In any case, there is no agreement on the physical properties of the domains where newly released Aβ binds membranes in cells.…”

N-Formylation modifies membrane damage associated with PSMα3 interfacial fibrillation

“…Such fluidity-dependent fibrillation and toxicity of amyloids have been previously reported for pathological amyloids. For instance, while fluid POPC or liquid-expanded DPPC (at T > T m ) facilitates fibrillation of Aβ by favouring high mobility of the peptides, the liquid-condensed phase of DPPC can retard their self-aggregation, 56 fibrils can even be excluded from such domains in lipid monolayers. 57 Besides, in these fluid membranes, our results point to a membrane perturbation, either as thinning or formation of holes, induced by PSMα3 once a threshold concentration of peptides is reached.…”

N-formylation modifies membrane damage associated to PSMα3 interfacial fibrillation

“…Such fluidity-dependent fibrillation and toxicity of amyloids have been previously reported for pathological amyloids. For instance, while fluid POPC or liquid-expanded DPPC (at T > Tm) facilitates fibrillation of Aβ by favouring a high mobility of the peptides, the liquid-condensed phase of DPPC can retard their self-aggregation 55 , fibrils can even be excluded from such domains in lipid monolayers 56 . Besides, in these fluid membranes, our results point to a membrane perturbation, either as thinning or formation of holes, induced by PSMα3 once a threshold concentration of peptides is reached.…”