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

Human serum albumin (HSA) is an important binding partner of amyloid-beta (A beta) in vivo and it can modulate A beta aggregation. However, the underlying molecular mechanism of this HSA-mediated modulation of Ab aggregation and cytotoxicity is still not fully understood, especially that of A beta 42, which is the most amyloidogenic and toxic A beta variant. For this reason, we systematically investigated the effect of HSA on the fibrillation and cytotoxicity of different A beta 42 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 A beta 42 species. Collective results indicated several important findings as follows: (i) HSA inhibited the fibrillation of the A beta 42 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 A beta 42 protofibrils and fibrils with increased affinity and formed HSA-A beta complexes that dissociated at a slower rate than the complex formed between HSA and the A beta 42 monomer; (iv) HSA prevented seeding-mediated cytotoxicity of A beta 42. Taken together, these findings suggested that the HSA inhibited A beta 42 fibrillation and cytotoxicity through interfering with different stages of A beta 42 fibrillation and targeting different A beta 42 intermediate aggregates. Furthermore, HSA preferentially interacted with A beta 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 A beta, and provide important implications for further designing HSA-based therapeutic strategies.