科研之友
微信
新浪微博
Facebook
分享链接
摘要
Aggregation of amyloid beta-proteins (A beta) 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+-A beta species have higher tendency to generate neurotoxic aggregates. Hence it is of significance to develop potent agents that inhibit Cu2+-mediated A beta aggregation under a mildly acidic condition. Herein we synthesized acid-ulated human serum albumin (A-HSA) to mitigate Cu2+ -mediated A beta(42) aggregation and cytotoxicity at pH 6.6. Extensive experiments showed that A-HSA altered the pathway of Cu2+-mediated A beta(42) aggregation and protected SH-SY5Y cells from cytotoxicity and oxidative damage induced by Cu2+ -A beta(42) species. Equimolar AHSA increased cell viability from 52% to 91% as compared to Cu2+-A beta(42)-treated group. Stopped-flow fluorescence analysis revealed that A-HSA changed the Cu2+-A beta(42) coordination mode from component I to II on the second timescale at pH 6.6, which avoided the formation of aggregation-prone Cu2+-A beta(42) aggregates. The findings revealed that the more negative charges on A-HSA surface could stabilize the protonated form of the adjacent histidine residues of A beta(42). 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 A beta(42) on A-HSA surface. The two opposite forces stretched A beta(42) conformations, which inhibited the formation of toxic Cu2+-A beta(42) aggregates. Thus, A-HSA worked as a bifunctional inhibitor against Cu2+-mediated A beta(42) aggregation and cytotoxicity under a mildly acidic condition.
