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

ABSTRACT

Amyloid-beta (Aß) oligomers are thought to be causative for the development and progression of Alzheimer's disease (AD). Starting from the Aß 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 Aß(1-42) to further enhance the Aß 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 Aß(1-42), eliminated Aß(1-42) oligomers, inhibited Aß(1-42) fibril formation, and reduced Aß(1-42)-induced cytotoxicity more efficiently than D3. Additionally, ANK6 completely inhibited the prion-like propagation of preformed Aß(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 Aß monomers and thereby induced elimination of Aß oligomers is a suitable therapeutic strategy.