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 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.
Institute of Complex Systems, Structural Biochemistry (ICS-6), Research Center Jülich, 52425, Jülich, Germany.
Antonia Nicole
AN
Klein
Institute of Complex Systems, Structural Biochemistry (ICS-6), Research Center Jülich, 52425, Jülich, Germany.
Tamar
T
Ziehm
Institute of Complex Systems, Structural Biochemistry (ICS-6), Research Center Jülich, 52425, Jülich, Germany.
Markus
M
Tusche
Institute of Complex Systems, Soft Matter (ICS-3), Research Center Jülich, 52425, Jülich, Germany.
Johan
J
Buitenhuis
Institute of Complex Systems, Structural Biochemistry (ICS-6), Research Center Jülich, 52425, Jülich, Germany.
Dirk
D
Bartnik
Neuroproteomforschung und Molekulare Mechanismen Neurodegenerativer Erkrankungen, Max-Delbrück-Centrum für Molekulare Medizin, Berlin, Germany.
Annett
A
Boeddrich
Neuroproteomforschung und Molekulare Mechanismen Neurodegenerativer Erkrankungen, Max-Delbrück-Centrum für Molekulare Medizin, Berlin, Germany.
Thomas
T
Wiglenda
Neuroproteomforschung und Molekulare Mechanismen Neurodegenerativer Erkrankungen, Max-Delbrück-Centrum für Molekulare Medizin, Berlin, Germany.
Erich
E
Wanker
Institute of Complex Systems, Structural Biochemistry (ICS-6), Research Center Jülich, 52425, Jülich, Germany.|Bioanalytik, Fakultät angewandte Naturwissenschaften, Hochschule für angewandte Wissenschaften Coburg, 96450, Coburg, Germany.
Susanne Aileen
SA
Funke
Institute of Complex Systems, Structural Biochemistry (ICS-6), Research Center Jülich, 52425, Jülich, Germany.|Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, 40225, Düsseldorf, Germany.
Oleksandr
O
Brener
Institute of Complex Systems, Structural Biochemistry (ICS-6), Research Center Jülich, 52425, Jülich, Germany.|Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, 40225, Düsseldorf, Germany.
Lothar
L
Gremer
Institute of Complex Systems, Structural Biochemistry (ICS-6), Research Center Jülich, 52425, Jülich, Germany.
Janine
J
Kutzsche
Institute of Complex Systems, Structural Biochemistry (ICS-6), Research Center Jülich, 52425, Jülich, Germany.|Institut für Physikalische Biologie, Heinrich-Heine-Universität Düsseldorf, 40225, Düsseldorf, Germany.
Dieter
D
Willbold
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry*; D000818:Animals; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D009842:Oligopeptides / Q000737:chemistry*; D051381:Rats
D016229:Amyloid beta-Peptides; D009842:Oligopeptides