Human Serum Albumin Inhibits Aβ Fibrillization through a Monomer-Competitor Mechanism

Human serum albumin (HSA) is not only a fatty acid and drug carrier protein, it is also a potent inhibitor of A beta self-association in plasma. However, the mechanism underlying the inhibition of A beta fibrillization by HSA is still not fully understood. We therefore investigated the A beta-HSA system using a combined experimental strategy based on saturation transfer difference (STD) NMR and intrinsic albumin fluorescence experiments on three A beta peptides with different aggregation propensities (i.e., A beta(12-28), A beta(1-40), and A beta(1-42)). Our data consistently show that albumin selectively binds to cross-beta-structured A beta oligomers as opposed to A beta monomers. The HSA/A beta oligomer complexes have K-D values in the micromolar to submicromolar range and compete with the further addition of A beta monomers to the A beta assemblies, thus inhibiting fibril growth (monomer competitor model). Other putative mechanisms, according to which albumin acts as a monomer stabilizer or a dissociation catalyst, are not supported by our data, thus resolving previous discrepancies in the literature regarding A beta-HSA interactions. In addition, the model and the experimental approaches proposed here are anticipated to have broad relevance for the characterization of other systems that involve amyloidogenic peptides and oligomerization inhibitors.