Structure-neurotoxicity relationships of amyloid beta-protein oligomers.
Amyloid beta-protein (Abeta) oligomers may be the proximate neurotoxins in Alzheimer's disease (AD). "Oligomer" is an ill-defined term because many kinds have been reported and they often exist in rapid equilibrium with monomers and higher-order assemblies. We report here results of studies in which specific oligomers have been stabilized structurally, fractionated in pure form, and then studied by using a combination of CD spectroscopy, Thioflavin T fluorescence, EM, atomic force microscopy (AFM), and neurotoxicity assays. Abeta monomers were largely unstructured, but oligomers exhibited order-dependent increases in beta-sheet content. EM and AFM data suggest that dimerization and subsequent monomer addition are processes in which significant and asymmetric monomer conformational changes occur. Oligomer secondary structure and order correlated directly with fibril nucleation activity. Neurotoxic activity increased disproportionately (order dependence >1) with oligomer order. The structure-activity correlations reported here significantly extend our understanding of the conformational dynamics, structure, and relative toxicity of pure Abeta oligomers of specific order.
Ono
Kenjiro
K
Department of Neurology, David Geffen School of Medicine, and Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA.
Condron
Margaret M
MM
Teplow
David B
DB
D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity* / Q000648:ultrastructure; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002942:Circular Dichroism; D006836:Hydro-Lyases / Q000378:metabolism; D018625:Microscopy, Atomic Force; D008854:Microscopy, Electron; D009498:Neurotoxins / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D016716:PC12 Cells; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D051381:Rats; D013329:Structure-Activity Relationship
D016229:Amyloid beta-Peptides; D009498:Neurotoxins; D006836:Hydro-Lyases; C045581:lactate dehydratase
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