Optimization of d -Peptides for Aβ Monomer Binding Specificity Enhances Their Potential to Eliminate Toxic Aβ Oligomers

Academic Article


  • Amyloid-beta (Aβ) oligomers are thought to be causative for the development and progression of Alzheimer's disease (AD). Starting from the Aβ oligomer eliminating d-enantiomeric peptide D3, we developed and applied a two-step procedure based on peptide microarrays to identify D3 derivatives with increased binding affinity and specificity for monomeric Aβ(1-42) to further enhance the Aβ oligomer elimination efficacy. Out of more than 1000 D3 derivatives, we selected seven novel d-peptides, named ANK1 to ANK7, and characterized them in more detail in vitro. All ANK peptides bound to monomeric Aβ(1-42), eliminated Aβ(1-42) oligomers, inhibited Aβ(1-42) fibril formation, and reduced Aβ(1-42)-induced cytotoxicity more efficiently than D3. Additionally, ANK6 completely inhibited the prion-like propagation of preformed Aβ(1-42) seeds and showed a nonsignificant tendency for improving memory performance of tg-APPSwDI mice after i.p. application for 4 weeks. This supports the hypothesis that stabilization of Aβ monomers and thereby induced elimination of Aβ oligomers is a suitable therapeutic strategy.
  • Authors

    Published In

    Digital Object Identifier (doi)

    Author List

  • Klein AN; Ziehm T; Van Groen T; Kadish I; Elfgen A; Tusche M; Thomaier M; Reiss K; Brener O; Gremer L
  • Start Page

  • 1889
  • End Page

  • 1900
  • Volume

  • 8
  • Issue

  • 9