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

This title appears in the Scientific Report : 2016

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

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 thera...

Personal Name(s):	Klein, Antonia Nicole
	Ziehm, Tamar / Tusche, Markus / Buitenhuis, Johan / Bartnik, Dirk / Boeddrich, Annett / Wiglenda, Thomas / Wanker, Erich / Funke, Susanne Aileen / Brener, Oleksandr / Gremer, Lothar / Kutzsche, Janine / Willbold, Dieter (Corresponding author)
Contributing Institute:	Weiche Materie; ICS-3 Strukturbiochemie; ICS-6
Published in:	PLoS one, 11 (2016) 4, S. e0153035 -
Imprint:	Lawrence, Kan. PLoS 2016
DOI:	10.1371/journal.pone.0153035
Document Type:	Journal Article
Research Program:	Functional Macromolecules and Complexes Physical Basis of Diseases
Link:	OpenAccess OpenAccess
	Publikationsportal JuSER

Please use the identifier: http://hdl.handle.net/2128/10957 in citations.
Please use the identifier: http://dx.doi.org/10.1371/journal.pone.0153035 in citations.

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.