Self-assembly of beta-amyloid 42 is retarded by small molecular ligands at the stage of structural intermediates

Détails

ID Serval
serval:BIB_416620AD7076
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Self-assembly of beta-amyloid 42 is retarded by small molecular ligands at the stage of structural intermediates
Périodique
Journal of Structural Biology
Auteur(s)
Bohrmann  B., Adrian  M., Dubochet  J., Kuner  P., Muller  F., Huber  W., Nordstedt  C., Dobeli  H.
ISSN
1047-8477 (Print)
Statut éditorial
Publié
Date de publication
06/2000
Volume
130
Numéro
2-3
Pages
232-46
Notes
Journal Article --- Old month value: Jun
Résumé
Assemblyof the amyloid-beta peptide (Abeta) into fibrils and its deposition in distinct brain areas is considered responsible for the pathogenesis of Alzheimer's disease (AD). Thus, inhibition of fibril assembly is a potential strategy for therapeutic intervention. Electron cryomicroscopy was used to monitor the initial, native assembly structure of Abeta42. In addition to the known fibrillar intermediates, a nonfibrillar, polymeric sheet-like structure was identified. A temporary sequence of supramolecular structures was revealed with (i) polymeric Abeta42 sheets during the onset of assembly, inversely related to the appearance of (ii) fibril intermediates, which again are time-dependently replaced by (iii) mature fibrils. A cell-based primary screening assay was used to identify compounds that decrease Abeta42-induced toxicity. Hit compounds were further assayed for binding to Abeta42, radical scavenger activity, and their influence on the assembly structure of Abeta42. One compound, Ro 90-7501, was found to efficiently retard mature fibril formation, while extended polymeric Abeta42 sheets and fibrillar intermediates are accumulated. Ro 90-7501 may serve as a prototypic inhibitor for Abeta42 fibril formation and as a tool for studying the molecular mechanism of fibril assembly.
Mots-clé
Amyloid beta-Protein/chemistry/*metabolism/*ultrastructure Benzimidazoles/chemistry/metabolism/pharmacology Cryoelectron Microscopy Free Radical Scavengers/chemistry/metabolism/*pharmacology Humans Ligands Molecular Structure Protein Binding Protein Conformation/drug effects Structure-Activity Relationship Surface Plasmon Resonance Time Factors
Pubmed
Web of science
Création de la notice
24/01/2008 11:25
Dernière modification de la notice
03/03/2018 16:32
Données d'usage