Mapping the Interactions between the Alzheimer's Aβ-Peptide and Human Serum Albumin beyond Domain Resolution

Human serum albumin (HSA) is a potent inhibitor of A beta self-association and this novel, to our knowledge, function of HSA is of potential therapeutic interest for the treatment of Alzheimer's disease. It is known that HSA interacts with A beta oligomers through binding sites evenly partitioned across the three albumin domains and with comparable affinities. However, as of this writing, no information is available on the HSA-A beta interactions beyond domain resolution. Here, we map the HSA-A beta interactions at subdomain and peptide resolution. We show that each separate subdomain of HSA domain 3 inhibits A beta self-association. We also show that fatty acids (FAs) compete with A beta oligomers for binding to domain 3, but the determinant of the HSA/A beta oligomer interactions are markedly distinct from those of FAs. Although salt bridges with the FA carboxylate determine the FA binding affinities, hydrophobic contacts are pivotal for A beta oligomer recognition. Specifically, we identified a site of A beta oligomer recognition that spans the HSA (494-515) region and aligns with the central hydrophobic core of A beta. The HSA (495-515) segment includes residues affected by FA binding and this segment is prone to self-associate into beta-amyloids, suggesting that sites involved in fibrilization may provide a lead to develop inhibitors of A beta self-association.