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-beta (A beta) conformations in membranes rich in omega-3 and omega-6 phospholipids. Herein, the structural properties of the A beta(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 alpha-helix, both omega-6 and omega-3 membranes promote new orientations and conformations of the dimer, in agreement with the observed dependence of A beta 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 beta-sheet, omega-6 membrane promotes helical and disordered structures of A beta(29-42) dimer, whereas omega-3 membrane preserves the beta-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 A beta(29-42) dimer. This finding demonstrates that variation in the abundance of the molecular phospholipids, which changes with age, modulates membrane-embedded A beta oligomerization.