Competitive Mirror Image Phage Display Derived Peptide Modulates Amyloid Beta Aggregation and Toxicity

Abstract

Alzheimer´s disease is the most prominent type of dementia and currently no causative treatment is available. According to recent studies, oligomeric species of the amyloid beta (Aβ) peptide appear to be the most toxic Aβ assemblies. Aβ monomers, however, may be not toxic per se and may even have a neuroprotective role. Here we describe a competitive mirror image phage display procedure that allowed us to identify preferentially Aβ1–42 monomer binding and thereby stabilizing peptides, which destabilize and thereby eliminate toxic oligomer species. One of the peptides, called Mosd1 (monomer specific d-peptide 1), was characterized in more detail. Mosd1 abolished oligomers from a mixture of Aβ1–42 species, reduced Aβ1–42 toxicity in cell culture, and restored the physiological phenotype in neuronal cells stably transfected with the gene coding for human amyloid precursor protein.

Optimization of d-Peptides for Aβ Monomer Binding Specificity Enhances Their Potential to Eliminate Toxic Aβ Oligomers

“…In the past, we started several intents to carry out such optimization and to confirm the proof of principle. First, we identified Aβ monomer specific ligands by repeating the original mirror image phage display selection procedure, but introducing additional counter-selection pressure for binding to Aβ oligomers and fibrils . Second, we set out to exchange every amino acid residue of D3 with all proteinogenic, except cysteine, in d -enantiomeric confirmation .…”

“…First, we identified Aβ monomer specific ligands by repeating the original mirror image phage display selection procedure, 8 but introducing additional counter-selection pressure for binding to Aβ oligomers and fibrils. 29 Second, we set out to exchange every amino acid residue of D3 with all proteinogenic, except cysteine, in D-enantiomeric confirmation. 30 In a second round, these replacements were combined for further selection.…”

Selection and Characterization of Tau Binding ᴅ-Enantiomeric Peptides with Potential for Therapy of Alzheimer Disease

“…In future, we plan to select peptides, which bind specifically to tau monomers and oligomers. Similar species specific peptides were earlier developed for conformers of the Aβ peptide [60,61]. Novel tau conformer specific peptides should be used to investigate in which stage of AD the inhibition of tau aggregation is reasonable and therapeutically helpful.…”

Brain Targeting and Aβ Binding Bifunctional Nanoparticles Inhibit Amyloid Protein Aggregation in APP/PS1 Transgenic Mice

“…Several studies have attempted to identify compounds that inhibit Aβ aggregation, and numerous neuroprotective peptide and protein drugs provide new hope for the treatment of AD. , However, 98 and 100% of small- and large-molecule drugs, respectively, including peptides, recombinant proteins, monoclonal antibodies, genes, and short interfering RNA cannot pass through the blood–brain barrier (BBB), , thus limiting drug development. The BBB prevents neurotoxins and microorganisms from entering the central nervous system (CNS) and selectively allows oxygen and other nutrients to pass through; thereby, it aids in maintaining homeostasis.…”