Stability of Aβ‐fibril fragments in the presence of fatty acids

Abstract

We consider the effect of lauric acid on the stability of various fibril‐like assemblies of Aβ peptides. For this purpose, we have performed molecular dynamics simulations of these assemblies either in complex with lauric acid or without presence of the ligand. While we do not observe a stabilizing effect on Aβ40‐fibrils, we find that addition of lauric acid strengthens the stability of fibrils built from the triple‐stranded S‐shaped Aβ42‐peptides considered to be more toxic. Or results may help to understand how the specifics of the brain‐environment modulate amyloid formation and propagation.

Effect of Lauric Acid on the Stability of Aβ42 Oligomers

“…Similar to what was seen by us in an earlier work, the ring-like oligomers of Model A type decay even in the presence of lauric acid and for the in-register arrangement of β 2 and β 3 strands much faster than the experiments in the Rangachari lab would let one expect. The situation is worse for Model B, where the individual chains take the form as seen in the Cryo-EM model (PDB ID: 5OQV) of an Aβ 42 fibril.…”

“…In ref , we proposed one of these ring-like assemblies, a six-fold double-layer (6 × 2) ring, as a structural model for the 12-mers, observed by the Rangachari Lab as the dominant species of their LFAOs in a low-concentration setting. Surprisingly, we did not find in ref a stabilization of this structure by the presence of lauric acid. For this reason, we have considered in the present study not only this model but also the one where in the individual chains, the β 2 and β 3 strands are in an out-of-register arrangement, replacing the inter-chain hydrogen bonds of the IRF geometry by intra-hydrogen bonds.…”

“…This result may either point to shortcomings in our model, which while consistent with experimental measurements of the Rangachari Lab may lack crucial details, or it may suggest that fatty acids shift the equilibrium toward toxic oligomers not by enhancing their stability but by a different mechanism. In order to probe this still open question and to explain the experimental results, we extend in the present paper our earlier work and study in more detail the effect of lauric acid on Aβ 42 oligomer models. Both ring-like and barrel-shaped models are considered as their pore-forming ability provides a potential mechanism for the presumed neurotoxicity of the oligomers.…”

“…In the case of Alzheimer’s disease, the effect of fatty acids seems to depend on the type: in a recent experiment, it was shown that a polyunsaturated fatty acid, omega-3, slows the progression of Alzheimer’s disease, whereas omega-6 increases the risk of Alzheimer’s disease. In ref , we could demonstrate that addition of lauric acid raises fibril stability for Aβ 42 , while no such stabilizing effect was found for Aβ 40 fibrils. Our results further suggested that the presence of lauric acid enhances the elongation of Aβ 42 fibrils but not their nucleation.…”