Structural studies of soluble oligomers of the Alzheimer beta-amyloid peptide.
Recent studies have suggested that non-fibrillar soluble forms of Abeta peptides possess neurotoxic properties and may therefore play a role in the molecular pathogenesis of Alzheimer's disease. We have identified solution conditions under which two types of soluble oligomers of Abeta40 could be trapped and stabilized for an extended period of time. The first type of oligomers comprises a mixture of dimers/tetramers which are stable at neutral pH and low micromolar concentration, for a period of at least four weeks. The second type of oligomer comprises a narrow distribution of particles that are spherical when examined by electron microscopy and atomic force microscopy. The number average molecular mass of this distribution of particles is 0.94 MDa, and they are are stable at pH 3 for at least four weeks. Circular dichroism studies indicate that the dimers/tetramers possess irregular secondary structure that is not alpha-helix or beta-structure, while the 0.94 MDa particles contain beta-structure. Fluorescence resonance energy transfer experiments indicate that Abeta40 moieties in amyloid fibrils or protofibrils are more similar in structure to those in the 0.94 MDa particles than those in the dimers/tetramers. These findings indicate that soluble oligomeric forms of Abeta peptides can be trapped for extended periods of time, enabling their study by high resolution techniques that would not otherwise be possible.
Huang
T H
TH
Division of Molecular and Structural Biology, Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M5G 2M9, Canada.
Yang
D S
DS
Plaskos
N P
NP
Go
S
S
Yip
C M
CM
Fraser
P E
PE
Chakrabartty
A
A
D000544:Alzheimer Disease; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D002942:Circular Dichroism; D019281:Dimerization; D005456:Fluorescent Dyes; D006801:Humans; D006863:Hydrogen-Ion Concentration; D018625:Microscopy, Atomic Force; D008854:Microscopy, Electron; D008970:Molecular Weight; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism* / Q000648:ultrastructure; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D012995:Solubility; D013050:Spectrometry, Fluorescence; D013816:Thermodynamics; D013997:Time Factors; D014461:Ultracentrifugation
D016229:Amyloid beta-Peptides; D005456:Fluorescent Dyes; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40)