Abstract
Alzheimer's Disease (AD) progresses with the formation of neuronal plaques composed primarily of the 42-residue alloform of amyloid-β (Aβ(42)), whose oligomeric forms induce cytotoxicity by interacting with neuronal membranes, resulting in permeabilization and calcium ion leakage. In AD, elevated phospholipase activity disrupts lipid homeostasis and may increase the concentration of free lipids, such as 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), in extracellular environments proximal to the membrane surface, potentially promoting Aβ(42) insertion and toxicity. The coaggregation of Aβ(42) with free lipids is believed to modulate mechanisms underlying Aβ(42)-induced cytotoxicity; however, these interactions are poorly understood. Molecular dynamics (MD) simulations were conducted to investigate Aβ(42)-POPC interactions and study the aggregation and structural morphologies of hexameric, octameric, and decameric Aβ(42) in conjunction with free POPC in a 1:1 ratio. Clustering, radius of gyration, and eccentricity analyses revealed that POPC modulates Aβ(42) oligomer morphology in a size-dependent manner. POPC increased compactness and sphericity in octameric and decameric systems, but had minimal or variable effects on hexamers. Hydrophobic interactions between Aβ(42) and POPC hydrocarbon tails drove co-oligomerization, and increased hydrophobic solvent accessibility of Aβ(42) peptides, altering the energetic profiles of hydrophobic and aromatic residues. To this effect, we hypothesize that Aβ(42) coaggregation with POPC may nucleate additional oligomerization events through hydrophobic exposure of Aβ(42). This work provides a mechanistic basis for early Aβ(42) oligomerization events in lipid microenvironments, offering insights into neurodegenerative pathology.