Kinetic studies of inhibition of the amyloid beta (1-42) aggregation using a ferrocene-tagged β-sheet breaker peptide

The aggregation of amyloidogenic proteins/peptides has been closely linked to the neuropathology of several important neurological disorders. In Alzheimer's disease, amyloid beta (A beta) 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 A beta(1-42) peptide responsible for beta-sheet stacking (referred to as the beta-sheet breaker peptides). Here, a water-soluble ferrocene (Fc)-tagged beta-sheet breaker peptide, Fc-KLVFFK6, was used as an electrochemical probe for kinetic studies of the inhibition of the A beta(1-42) fibrillation process and for determination of the optimal concentration of beta-sheet breaker peptide for efficient inhibition. Our results demonstrate that Fc-KLVFFK6 interacts with the A beta aggregates instantaneously in solution, and a sub-stoichiometric amount of Fc-KLVFFK6 is sufficient to inhibit the formation of the A beta oligomers and fibrils and to reduce the toxicity of A beta(1-42). The interaction between Fc-KLVFFK6 and A beta(1-42) follows a pseudo-first-order reaction, with a rate constant of 1.89 +/- 0.05 x 10(-4) s(-1). Tagging beta-sheet breaker peptides with a redox label facilitates design, screening, and rational use of peptidic inhibitors for impeding/altering A beta aggregation. Published by Elsevier Inc.