title: Insight into the inhibition effect of acidulated serum albumin on amyloid β-protein fibrillogenesis and cytotoxicity.
abstract: Alzheimer's disease (AD) is the most prevalent form of dementia, and aggregation of amyloid β-proteins (Aβ) into soluble oligomers and fibrils has been implicated in the pathogenesis of AD. Herein we developed acidulated serum albumin for the inhibition of Aβ42 fibrillogenesis. Bovine serum albumin (BSA) was modified with diglycolic anhydride, leading to the coupling of 14.5 more negative charges (carboxyl groups) on average on each protein surface. The acidulated BSA (A-BSA) was characterized and confirmed to keep the tertiary structure and stability of BSA. Extensive biophysical and biological analyses showed that A-BSA significantly inhibited Aβ42 fibrillogenesis and mitigated amyloid cytotoxicity. As compared to the Aβ42-treated group (cell viability, 50%), the cell viability increased to 88% by the addition of equimolar A-BSA. The inhibitory effect was remarkably higher than that of BSA at the same concentration. On the basis of the experimental findings, a mechanistic model was proposed. The model considers that Aβ42 is bound to the A-BSA surface by hydrophobic interactions, but the widely distributed negative charges on the A-BSA surface give rise to electrostatic repulsions to the bound Aβ42 that is also negatively charged. The two well-balanced opposite forces make Aβ42 adopt extended conformations instead of the β-sheet structure that is necessary for the on-pathway fibrillogenesis, even when the protein is released off the surface. Thus, A-BSA greatly slows down the fibrillation and changes the fibrillogenesis pathway, leading to the formation of less toxic aggregates. The findings and the mechanistic model offer new insights into the development of more potent inhibitors of Aβ fibrillogenesis and cytotoxicity.
authors.affiliation: Department of Biochemical Engineering and Key Laboratory of Systems Bioengineering of the Ministry of Education, School of Chemical Engineering and Technology, Tianjin University , Tianjin 300072, China.
authors.forename: Baolong
authors.initials: B
authors.lastname: Xie
authors.forename: Xi
authors.initials: X
authors.lastname: Li
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Dong
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D016716:PC12 Cells; D051381:Rats; D012710:Serum Albumin, Bovine / Q000009:adverse effects / Q000737:chemistry*
chemical_list: D016229:Amyloid beta-Peptides; D012710:Serum Albumin, Bovine