Structural Characteristics of Docosahexaenoic Acid and Eicosapentaenoic Acid Inhibiting Amyloid-β Fibrillation

Alzheimer's disease is a neurodegenerative disease whose pathological hallmark is the fibrilization of the amyloid-β (Aβ) peptides. Omega-3 (n-3) polyunsaturated fatty acids (PUFAs), including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), inhibit the Aβ aggregation in vitro; however, the molecular basis for the inhibition remained unclear. In this study, we analyzed the interactions of n-3 PUFAs with the partial peptides of 42-residue Aβ via molecular simulations. The analysis predicted that DHA and EPA were preferred over their derivatives in terms of the calculated free energy changes of the ligand–Aβ binding. The results of our simulations were validated using experimental methods, and the structural characteristics identified in in silico analysis were also confirmed to be important elements inin vitro experiments. This study enabled a mechanistic understanding of n-3 PUFAs to protect against Aβ fibril formation and offer a molecular basis for designing therapeutics against Alzheimer's disease.