Structural Conversion of Neurotoxic Amyloid-beta(1-42) Oligomers to Fibrils

Overview

Journal Nat Struct Mol Biol

Specialties Cell Biology
Molecular Biology

Date 2010 Apr 13

PMID 20383142

Citations 435

Authors

Mahiuddin Ahmed

Judianne Davis

Darryl Aucoin

Takeshi Sato

Shivani Ahuja

Saburo Aimoto

James I Elliott

William E Van Nostrand

Steven O Smith

Affiliations

Soon will be listed here.

Abstract

The amyloid-beta(1-42) (Abeta42) peptide rapidly aggregates to form oligomers, protofibils and fibrils en route to the deposition of amyloid plaques associated with Alzheimer's disease. We show that low-temperature and low-salt conditions can stabilize disc-shaped oligomers (pentamers) that are substantially more toxic to mouse cortical neurons than protofibrils and fibrils. We find that these neurotoxic oligomers do not have the beta-sheet structure characteristic of fibrils. Rather, the oligomers are composed of loosely aggregated strands whose C termini are protected from solvent exchange and which have a turn conformation, placing Phe19 in contact with Leu34. On the basis of NMR spectroscopy, we show that the structural conversion of Abeta42 oligomers to fibrils involves the association of these loosely aggregated strands into beta-sheets whose individual beta-strands polymerize in a parallel, in-register orientation and are staggered at an intermonomer contact between Gln15 and Gly37.

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