Source:http://linkedlifedata.com/resource/pubmed/id/10940228
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| Predicate | Object |
|---|---|
| rdf:type | |
| lifeskim:mentions | |
| pubmed:issue |
2-3
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| pubmed:dateCreated |
2000-12-11
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| pubmed:abstractText |
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.
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| pubmed:language |
eng
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| pubmed:journal | |
| pubmed:citationSubset |
IM
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| pubmed:chemical | |
| pubmed:status |
MEDLINE
|
| pubmed:month |
Jun
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| pubmed:issn |
1047-8477
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| pubmed:author | |
| pubmed:copyrightInfo |
Copyright 2000 Academic Press.
|
| pubmed:issnType |
Print
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| pubmed:volume |
130
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| pubmed:owner |
NLM
|
| pubmed:authorsComplete |
Y
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| pubmed:pagination |
232-46
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| pubmed:dateRevised |
2010-11-18
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| pubmed:meshHeading |
pubmed-meshheading:10940228-Amyloid beta-Peptides,
pubmed-meshheading:10940228-Benzimidazoles,
pubmed-meshheading:10940228-Cryoelectron Microscopy,
pubmed-meshheading:10940228-Free Radical Scavengers,
pubmed-meshheading:10940228-Humans,
pubmed-meshheading:10940228-Ligands,
pubmed-meshheading:10940228-Molecular Structure,
pubmed-meshheading:10940228-Protein Binding,
pubmed-meshheading:10940228-Protein Conformation,
pubmed-meshheading:10940228-Structure-Activity Relationship,
pubmed-meshheading:10940228-Surface Plasmon Resonance,
pubmed-meshheading:10940228-Time Factors
|
| pubmed:year |
2000
|
| pubmed:articleTitle |
Self-assembly of beta-amyloid 42 is retarded by small molecular ligands at the stage of structural intermediates.
|
| pubmed:affiliation |
Pharma Division, F. Hoffmann-La Roche AG, Basel, CH-4070, Switzerland. bernd.bohrmann@roche.com
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| pubmed:publicationType |
Journal Article
|