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...
Main Authors: | , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Public Library of Science (PLoS)
2016-01-01
|
Series: | PLoS ONE |
Online Access: | http://europepmc.org/articles/PMC4841555?pdf=render |
id |
doaj-083680e70c82443787f8e0d46841487d |
---|---|
record_format |
Article |
spelling |
doaj-083680e70c82443787f8e0d46841487d2020-11-25T02:33:21ZengPublic Library of Science (PLoS)PLoS ONE1932-62032016-01-01114e015303510.1371/journal.pone.0153035Optimization of the All-D Peptide D3 for Aβ Oligomer Elimination.Antonia Nicole KleinTamar ZiehmMarkus TuscheJohan BuitenhuisDirk BartnikAnnett BoeddrichThomas WiglendaErich WankerSusanne Aileen FunkeOleksandr BrenerLothar GremerJanine KutzscheDieter WillboldThe 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.http://europepmc.org/articles/PMC4841555?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 Dieter Willbold |
spellingShingle |
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 Dieter Willbold Optimization of the All-D Peptide D3 for Aβ Oligomer Elimination. PLoS ONE |
author_facet |
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 Dieter Willbold |
author_sort |
Antonia Nicole Klein |
title |
Optimization of the All-D Peptide D3 for Aβ Oligomer Elimination. |
title_short |
Optimization of the All-D Peptide D3 for Aβ Oligomer Elimination. |
title_full |
Optimization of the All-D Peptide D3 for Aβ Oligomer Elimination. |
title_fullStr |
Optimization of the All-D Peptide D3 for Aβ Oligomer Elimination. |
title_full_unstemmed |
Optimization of the All-D Peptide D3 for Aβ Oligomer Elimination. |
title_sort |
optimization of the all-d peptide d3 for aβ oligomer elimination. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2016-01-01 |
description |
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. |
url |
http://europepmc.org/articles/PMC4841555?pdf=render |
work_keys_str_mv |
AT antonianicoleklein optimizationofthealldpeptided3foraboligomerelimination AT tamarziehm optimizationofthealldpeptided3foraboligomerelimination AT markustusche optimizationofthealldpeptided3foraboligomerelimination AT johanbuitenhuis optimizationofthealldpeptided3foraboligomerelimination AT dirkbartnik optimizationofthealldpeptided3foraboligomerelimination AT annettboeddrich optimizationofthealldpeptided3foraboligomerelimination AT thomaswiglenda optimizationofthealldpeptided3foraboligomerelimination AT erichwanker optimizationofthealldpeptided3foraboligomerelimination AT susanneaileenfunke optimizationofthealldpeptided3foraboligomerelimination AT oleksandrbrener optimizationofthealldpeptided3foraboligomerelimination AT lothargremer optimizationofthealldpeptided3foraboligomerelimination AT janinekutzsche optimizationofthealldpeptided3foraboligomerelimination AT dieterwillbold optimizationofthealldpeptided3foraboligomerelimination |
_version_ |
1724814646713516032 |