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Keywords:

  • aggregation;
  • Alzheimer’s disease;
  • inhibitors;
  • peptides;
  • protein engineering

Abstract

Aggregation of amyloid β-peptide (Aβ) is closely related to the pathogenesis of Alzheimer’s disease (AD). Although much effort has been devoted to the construction of molecules that inhibit the aggregation of Aβ1-42, high doses are needed for the inhibition of Aβ aggregation in many cases. Previously, we reported that designed green fluorescent protein (GFP) analogues that gives pseudo-Aβ β-sheet structures can work as an aggregation inhibitor against Aβ. To further test this design strategy, we constructed protein analogues that mimic Aβ β-sheet structures of amyloids by using insulin-like growth factor 2 receptor domain 11 (IGF2R-d11) as a scaffold. A designed protein, named IG11KK, which has a parallel configuration of Aβ-like β sheets, can bind more preferentially to oligomeric Aβ1-42 than the monomer. Moreover, IG11KK suppressed the aggregation of Aβ1-42 efficiently, even though lower concentrations of IG11KK than Aβ were used. The aggregation kinetics of Aβ in the presence of the designed proteins revealed that IG11KK can work as an inhibitor not only for the early to middle stages, but also in the latter stage of Aβ aggregation owing to its favorable binding to oligomeric structures of Aβ. The design strategy using β-barrel proteins such as IGF2R-d11 and GFP is useful in generating excellent inhibitors of protein misfolding and amyloid formation.