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Optimization of the All-D Peptide D3 for Aβ Oligomer Elimination.

By Antonia Nicole Klein, Tamar Ziehm, Markus Tusche, Johan Buitenhuis, Dirk Bartnik, Annett Boeddrich, Thomas Wiglenda, Erich Wanker, Susanne Aileen Funke, Oleksandr Brener, Lothar Gremer, Janine Kutzsche and Dieter Willbold

Abstract

The aggregation of amyloid-β (Aβ) is postulated to be the crucial event in Alzheimer's disease (AD). In particular, small neurotoxic Aβ oligomers are considered to be responsible for the development and progression of AD. Therefore, elimination of thesis oligomers represents a potential causal therapy of AD. Starting from the well-characterized d-enantiomeric peptide D3, we identified D3 derivatives that bind monomeric Aβ. The underlying hypothesis is that ligands bind monomeric Aβ and stabilize these species within the various equilibria with Aβ assemblies, leading ultimately to the elimination of Aβ oligomers. One of the hereby identified d-peptides, DB3, and a head-to-tail tandem of DB3, DB3DB3, were studied in detail. Both peptides were found to: (i) inhibit the formation of Thioflavin T-positive fibrils; (ii) bind to Aβ monomers with micromolar affinities; (iii) eliminate Aβ oligomers; (iv) reduce Aβ-induced cytotoxicity; and (v) disassemble preformed Aβ aggregates. The beneficial effects of DB3 were improved by DB3DB3, which showed highly enhanced efficacy. Our approach yielded Aβ monomer-stabilizing ligands that can be investigated as a suitable therapeutic strategy against AD

Topics: Medicine, R, Science, Q
Publisher: Public Library of Science (PLoS)
DOI identifier: 10.1371/journal.pone.0153035
OAI identifier: oai:doaj.org/article:083680e70c82443787f8e0d46841487d
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