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 Aβ self-association in plasma. However, the mechanism underlying the inhibition of Aβ fibrillization by HSA is still not fully understood. We therefore investigated the Aβ-HSA system using a combined experimental strategy based on saturation transfer difference (STD) NMR and intrinsic albumin fluorescence experiments on three Aβ peptides with different aggregation propensities (i.e., Aβ(12–28), Aβ(1–40), and Aβ(1–42)). Our data consistently show that albumin selectively binds to cross-β-structured Aβ oligomers as opposed to Aβ monomers. The HSA/Aβ oligomer complexes have KD values in the micromolar to submicromolar range and compete with the further addition of Aβ monomers to the Aβ 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 Aβ-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.