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A11-positive β-amyloid Oligomer Preparation and Assessment Using Dot Blotting Analysis
Published on: May 22, 2018
β-Hairpin mimics containing a piperidine-pyrrolidine scaffold modulate the β-amyloid aggregation process preserving
S Pellegrino1, N Tonali2, E Erba1
1DISFARM-Sez. Chimica Generale e Organica "A. Marchesini" , Universitá degli Studi di Milano , via Venezian 21 , 20133 Milano , Italy .
Abstract:
Alzheimer's disease is a neurodegenerative disorder linked to oligomerization and fibrillization of amyloid β peptides, with Aβ1-42 being the most aggregative and neurotoxic one. We report herein the synthesis and conformational analysis of Aβ1-42-amyloid related β-hairpin peptidomimetics, built on a piperidine-pyrrolidine semi rigid β-turn inducer and bearing two small recognition peptide sequences, designed on oligomeric and fibril structures of Aβ1-42. According to these peptide sequences, a stable β-hairpin or a dynamic equilibrium between two possible architectures was observed. These original constructs are able to greatly delay the kinetics of Aβ1-42 aggregation process as demonstrated by thioflavin-T fluorescence, and transmission electron microscopy. Capillary electrophoresis indicates their ability to preserve the monomer species, inhibiting the formation of toxic oligomers. Furthermore, compounds protect against toxic effects of Aβ on neuroblastoma cells even at substoichiometric concentrations. This study is the first example of acyclic small β-hairpin mimics possessing such a highly efficient anti-aggregation activity. The protective effect is more pronounced than that observed with molecules which have undergone clinical trials. The structural elements made in this study provide valuable insights in the understanding of the aggregation process and insights to explore the design of novel acyclic β-hairpin targeting other types of amyloid-forming proteins.
Insights
New acyclic β-hairpin mimics effectively inhibit amyloid β1-42 aggregation, a key factor in Alzheimer's disease. These compounds protect neurons from toxic effects, offering a promising therapeutic strategy.
Area of Science:
- Medicinal Chemistry
- Neuroscience
- Biochemistry
Background:
- Alzheimer's disease pathogenesis involves amyloid β (Aβ) peptide oligomerization and fibrillization, particularly the highly aggregative Aβ1-42.
- Developing inhibitors of Aβ1-42 aggregation is crucial for therapeutic intervention in Alzheimer's disease.
Purpose of the Study:
- To synthesize and analyze novel acyclic β-hairpin peptidomimetics designed to inhibit Aβ1-42 aggregation.
- To evaluate the efficacy of these peptidomimetics in preventing Aβ1-42-induced neurotoxicity.
Main Methods:
- Synthesis of piperidine-pyrrolidine based β-hairpin peptidomimetics with specific recognition sequences.
- Conformational analysis of the synthesized peptidomimetics.
- Thioflavin-T fluorescence assays, transmission electron microscopy, and capillary electrophoresis to assess Aβ1-42 aggregation kinetics and species.
- Neuroblastoma cell-based assays to evaluate protection against Aβ1-42 toxicity.
Main Results:
- The synthesized β-hairpin mimics demonstrated significant delay in Aβ1-42 aggregation kinetics.
- These compounds were shown to preserve monomeric Aβ species and inhibit the formation of toxic oligomers.
- Substoichiometric concentrations of the mimics provided substantial protection to neuroblastoma cells against Aβ1-42-induced toxicity, outperforming molecules in clinical trials.
Conclusions:
- Acyclic β-hairpin mimics represent a novel and highly efficient strategy for inhibiting Aβ1-42 aggregation and mitigating neurotoxicity.
- The structural insights gained provide a foundation for designing new acyclic β-hairpin inhibitors targeting other amyloidogenic proteins.
- These findings offer a promising therapeutic avenue for Alzheimer's disease and related protein misfolding disorders.
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