Amyloid-β(29-42) Dimeric Conformations in Membranes Rich in Omega-3 and Omega-6 Polyunsaturated Fatty Acids

The omega-3 and omega-6 polyunsaturated fatty acids are two important components of cell membranes in human brains. When incorporated into phospholipids, omega-3 slows the progression of Alzheimer's disease (AD), whereas omega-6 is linked to increased risk of AD. Little is known on the amyloid-β (Aβ) conformations in membranes rich in omega-3 and omega-6 phospholipids. Herein, the structural properties of the Aβ_29-42 dimer embedded in both fatty acid membranes were comparatively studied to a 1-palmitoyl-2-oleoyl- sn-glycero-3-phosphocholine (POPC) bilayer using all-atom molecular dynamics (MD) simulations. Starting from α-helix, both omega-6 and omega-3 membranes promote new orientations and conformations of the dimer, in agreement with the observed dependence of Aβ production upon addition of these two fatty acids. This conformational result is corroborated by atomistic MD simulations of the dimer of the 99 amino acid C-terminal fragment of amyloid precursor protein spanning the residues 15-55. Starting from β-sheet, omega-6 membrane promotes helical and disordered structures of Aβ_29-42 dimer, whereas omega-3 membrane preserves the β-sheet structures differing however from those observed in POPC. Remarkably, the mixture of the two fatty acids and POPC depicts another conformational ensemble of the Aβ_29-42 dimer. This finding demonstrates that variation in the abundance of the molecular phospholipids, which changes with age, modulates membrane-embedded Aβ oligomerization.