title: Modulation effect of acidulated human serum albumin on Cu2+-mediated amyloid β-protein aggregation and cytotoxicity under a mildly acidic condition.
abstract: Aggregation of amyloid β-proteins (Aβ) induced by Cu2+is a crucial element in the pathogenesis of Alzheimer's disease (AD), and cerebral acidosis is a common complication of AD. Under mildly acidic conditions, Cu2+-Aβ species have higher tendency to generate neurotoxic aggregates. Hence it is of significance to develop potent agents that inhibit Cu2+-mediated Aβ aggregation under a mildly acidic condition. Herein we synthesized acidulated human serum albumin (A-HSA) to mitigate Cu2+-mediated Aβ42aggregation and cytotoxicity at pH6.6. Extensive experiments showed that A-HSA altered the pathway of Cu2+-mediated Aβ42aggregation and protected SH-SY5Y cells from cytotoxicity and oxidative damage induced by Cu2+-Aβ42species. Equimolar A-HSA increased cell viability from 52% to 91% as compared to Cu2+-Aβ42-treated group. Stopped-flow fluorescence analysis revealed that A-HSA changed the Cu2+-Aβ42coordination mode from component I to II on the second timescale at pH6.6, which avoided the formation of aggregation-prone Cu2+-Aβ42aggregates. The findings revealed that the more negative charges on A-HSA surface could stabilize the protonated form of the adjacent histidine residues of Aβ42. Hence, component I, which is necessary to form toxic aggregates, became unstable in the presence of A-HSA. On the other hand, hydrophobic binding and electrostatic repulsion could work simultaneously on the bound Aβ42on A-HSA surface. The two opposite forces stretched Aβ42conformations, which inhibited the formation of toxic Cu2+-Aβ42aggregates. Thus, A-HSA worked as a bifunctional inhibitor against Cu2+-mediated Aβ42aggregation and cytotoxicity under a mildly acidic condition.
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 300354, China.
authors.forename: Baolong
authors.initials: B
authors.lastname: Xie
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 300354, China.
authors.forename: Fufeng
authors.initials: F
authors.lastname: Liu
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 300354, China. Electronic address: d_xy@tju.edu.cn.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Dong
authors.affiliation: Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Yongjian
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Biomedical Engineering, The University of Alabama at Birmingham, Birmingham, AL 35233, USA.
authors.forename: Xiaoguang Margaret
authors.initials: XM
authors.lastname: Liu
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 300354, China. Electronic address: ysun@tju.edu.cn.
authors.forename: Yan
authors.initials: Y
authors.lastname: Sun
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D003300:Copper / Q000378:metabolism* / Q000633:toxicity; D006801:Humans; D006863:Hydrogen-Ion Concentration; D046529:Microscopy, Electron, Transmission; D066263:Protein Aggregation, Pathological / Q000503:physiopathology*; D011485:Protein Binding; D012709:Serum Albumin / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D012709:Serum Albumin; D003300:Copper
keywords: Aggregation; Albumin; Amyloid β-protein; Copper ion; Mildly acidic condition; Negative charge