Optimization of the All-D peptide D3 for Aβ oligomer elimination

Klein, A.N.; Ziehm, T.; Tusche, M.; Buitenhuis, J.; Bartnik, D.; Boeddrich, A.; Wiglenda, T.; Wanker, E.; Funke, S.A.; Brener, O.; Gremer, L.; Kutzsche, J.; Willbold, D.

Optimization of the All-D peptide D3 for Aβ oligomer elimination

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Item Type:	Article
Title:	Optimization of the All-D peptide D3 for Aβ oligomer elimination
Creators Name:	Klein, A.N., Ziehm, T., Tusche, M., Buitenhuis, J., Bartnik, D., Boeddrich, A., Wiglenda, T., Wanker, E., Funke, S.A., Brener, O., Gremer, L., Kutzsche, J. and Willbold, D.
Abstract:	The aggregation of amyloid-{beta} (A{beta}) is postulated to be the crucial event in Alzheimer's disease (AD). In particular, small neurotoxic A{beta} 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 A{beta}. The underlying hypothesis is that ligands bind monomeric A{beta} and stabilize these species within the various equilibria with A{beta} assemblies, leading ultimately to the elimination of A{beta} 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 A{beta} monomers with micromolar affinities; (iii) eliminate A{beta} oligomers; (iv) reduce A{beta}-induced cytotoxicity; and (v) disassemble preformed A{beta} aggregates. The beneficial effects of DB3 were improved by DB3DB3, which showed highly enhanced efficacy. Our approach yielded A{beta} monomer-stabilizing ligands that can be investigated as a suitable therapeutic strategy against AD.
Keywords:	Amino Acid Sequence, Amyloid {beta}-Peptides, Enzyme-Linked Immunosorbent Assay, Oligopeptides, Tumor Cell Line, Animals, Rats
Source:	PLoS ONE
ISSN:	1932-6203
Publisher:	Public Library of Science
Volume:	11
Number:	4
Page Range:	e0153035
Date:	22 April 2016
Official Publication:	https://doi.org/10.1371/journal.pone.0153035
PubMed:	View item in PubMed

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