title: Kinetic studies of inhibition of the amyloid beta (1-42) aggregation using a ferrocene-tagged β-sheet breaker peptide.
abstract: The aggregation of amyloidogenic proteins/peptides has been closely linked to the neuropathology of several important neurological disorders. In Alzheimer's disease, amyloid beta (Aβ) peptides and their aggregation are believed to be at least partially responsible for the etiology of Alzheimer's disease. The aggregate-inflicted cellular toxicity can be inhibited by short peptides whose sequences are homologous to segments of the Aβ(1-42) peptide responsible for β-sheet stacking (referred to as the β-sheet breaker peptides). Here, a water-soluble ferrocene (Fc)-tagged β-sheet breaker peptide, Fc-KLVFFK(6), was used as an electrochemical probe for kinetic studies of the inhibition of the Aβ(1-42) fibrillation process and for determination of the optimal concentration of β-sheet breaker peptide for efficient inhibition. Our results demonstrate that Fc-KLVFFK(6) interacts with the Aβ aggregates instantaneously in solution, and a sub-stoichiometric amount of Fc-KLVFFK(6) is sufficient to inhibit the formation of the Aβ oligomers and fibrils and to reduce the toxicity of Aβ(1-42). The interaction between Fc-KLVFFK(6) and Aβ(1-42) follows a pseudo-first-order reaction, with a rate constant of 1.89 ± 0.05 × 10(-4) s(-1). Tagging β-sheet breaker peptides with a redox label facilitates design, screening, and rational use of peptidic inhibitors for impeding/altering Aβ aggregation.
authors.affiliation: College of Chemistry and Chemical Engineering, Central South University, Changsha, Hunan 410083, People's Republic of China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Gargey
authors.initials: G
authors.lastname: Yagnik
authors.forename: Yong
authors.initials: Y
authors.lastname: Peng
authors.forename: Jianxiu
authors.initials: J
authors.lastname: Wang
authors.forename: H Howard
authors.initials: HH
authors.lastname: Xu
authors.forename: Yuanqiang
authors.initials: Y
authors.lastname: Hao
authors.forename: You-Nian
authors.initials: YN
authors.lastname: Liu
authors.forename: Feimeng
authors.initials: F
authors.lastname: Zhou
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D005296:Ferrous Compounds / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D000075163:Metallocenes; D018625:Microscopy, Atomic Force; D010446:Peptide Fragments / Q000037:antagonists & inhibitors*; D010455:Peptides / Q000378:metabolism*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D012995:Solubility
chemical_list: D016229:Amyloid beta-Peptides; D005296:Ferrous Compounds; D000075163:Metallocenes; D010446:Peptide Fragments; D010455:Peptides; C075222:amyloid beta-protein (1-42); C004998:ferrocene