Self-assembly of beta-amyloid 42 is retarded by small molecular ligands at the stage of structural intermediates.
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.
Bohrmann
B
B
Pharma Division, F. Hoffmann-La Roche AG, Basel, CH-4070, Switzerland. bernd.bohrmann@roche.com
Adrian
M
M
Dubochet
J
J
Kuner
P
P
Müller
F
F
Huber
W
W
Nordstedt
C
C
Döbeli
H
H
D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism* / Q000648:ultrastructure*; D001562:Benzimidazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D020285:Cryoelectron Microscopy; D016166:Free Radical Scavengers / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D011485:Protein Binding; D011487:Protein Conformation / Q000187:drug effects; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D013997:Time Factors
D016229:Amyloid beta-Peptides; D001562:Benzimidazoles; D016166:Free Radical Scavengers; D008024:Ligands