Naproxen Interferes with the Assembly of A β Oligomers Implicated in Alzheimer's Disease

Abstract

Experimental and epidemiological studies have shown that the nonsteroidal antiinflammatory drug naproxen may be useful in the treatment of Alzheimer's disease. To investigate the interactions of naproxen with A β dimers, which are the smallest cytotoxic aggregated A β peptide species, we use united atom implicit solvent model and exhaustive replica exchange molecular dynamics. We show that naproxen ligands bind to A β dimer and penetrate its volume interfering with the interpeptide interactions. As a result naproxen induces a destabilizing effect on A β dimer. By comparing the free-energy landscapes of naproxen interactions with A β dimers and fibrils, we conclude that this ligand has stronger antiaggregation potential against A β fibrils rather than against dimers. The analysis of naproxen binding energetics shows that the location of ligand binding sites in A β dimer is dictated by the A β amino acid sequence. Comparison of the in silico findings with experimental observations reveals potential limitations of naproxen as an effective therapeutic agent in the treatment of Alzheimer's disease.