期刊
ACS CHEMICAL NEUROSCIENCE
卷 10, 期 3, 页码 1390-1401出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.8b00440
关键词
Alzheimer's disease; amyloid beta-protein; multifunctional inhibitor; D-enantiomeric peptide; chirality; oxidative stress
资金
- National Natural Science Foundation of China [91634119, 21621004]
Aggregation of amyloid beta-protein (A beta) into beta-sheet-rich plaques is a general feature of Alzheimers disease (AD). Homeostasis dysregulation of Cu2+ mediates A beta to form high cytotoxic aggregates, which causes cell damage by generation of reactive oxygen species (ROS). To improve the inhibitory potency and explore the multifaceted functions of our previously designed decapeptide, RTHLVFFARK-NH2 (RK10), we have herein reformulated the decapeptide into its d-enantiomer, rk10, and the effects of chirality on A beta aggregation, Cu2+-mediated A beta aggregations, and aggregate-remodeling effects were investigated. The results revealed the following: (1) The d-enantiomer presented enhanced inhibitory potency on A beta fibrillogenesis in comparison to RK10; rk10 and RK10 increased the cell viability from 60% to 91% and 71%, respectively, at an equimolar concentration to A beta. (2) The enantiomers were chemically equivalent to Cu2+ chelation, ROS suppression and oxidative damage rescue. (3) The d-enantiomer exhibited higher performance to inhibit Cu2+-mediated A beta aggregation, and more significantly attenuated the cytotoxicity caused by A beta(42)-Cu2+ complex than RK10. Cell viability was rescued from 51% to 89% and 74% by coincubating with rk10 and RK10 at 50 mu M, respectively. Intracellular ROS levels generated by A beta(42) and A beta(42)-Cu2+ species were also remarkably decreased by treating with rk10. (4) The enantiomers could remodel mature A beta(42)-Cu2+ aggregates by Cu2+ chelation, and rk10 showed higher performance than RK10, as evidenced by the enhanced cell viability from 57% to 86% by RK10 and to 96% by rk10. The d-enantiomer also showed higher ability than RK10 on protecting the disrupted species from reaggregation. Taken together, D-chiral derivatization of the decapeptide resulted in a potent multifunctional agent in inhibiting Cu2+-mediated A beta aggregation and remodeling mature A beta-Cu2+ species. To the best of our knowledge, this is the first investigation on the chirality effect of a multifunctional peptide inhibitor on Cu2+-mediated A beta aggregation and on the remodeling effect of mature A beta-Cu2+ aggregates. The work provides new insights into the critical role of chirality in the multifaceted functions of peptide inhibitors against amyloid formation and its toxicity.
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