HSA targets multiple Aβ42 species and inhibits the seeding-mediated aggregation and cytotoxicity of Aβ42 aggregates

Abstract

Human serum albumin (HSA) is an important binding partner of amyloid-β (Aβ) in vivo and it can modulate Aβ aggregation. However, the underlying molecular mechanism of this HSA-mediated modulation of Aβ aggregation and cytotoxicity is still not fully understood, especially that of Aβ42, which is the most amyloidogenic and toxic Aβ variant. For this reason, we systematically investigated the effect of HSA on the fibrillation and cytotoxicity of different Aβ42 aggregation species in the amyloid-formation pathways by extensive biophysical and biological tests. Moreover, a Surface Plasmon Resonance (SPR) assay was performed to determine the ability of HSA to bind to different Aβ42 species. Collective results indicated several important findings as follows: (i) HSA inhibited the fibrillation of the Aβ42 monomer in a concentration-dependent manner; (ii) HSA abolished the seeding ability of protofibril and fibril at a 1 : 1 molar ratio; (iii) HSA interacted with Aβ42 protofibrils and fibrils with increased affinity and formed HSA–Aβ complexes that dissociated at a slower rate than the complex formed between HSA and the Aβ42 monomer; (iv) HSA prevented seeding-mediated cytotoxicity of Aβ42. Taken together, these findings suggested that the HSA inhibited Aβ42 fibrillation and cytotoxicity through interfering with different stages of Aβ42 fibrillation and targeting different Aβ42 intermediate aggregates. Furthermore, HSA preferentially interacted with Aβ fibrillar aggregates to form slowly-dissociated complexes. These findings contributed to a better understanding of the molecular mechanism by which HSA modulates the aggregation and cytotoxicity of Aβ, and provide important implications for further designing HSA-based therapeutic strategies.