Contribution of simple saccharides to the stabilization of amyloid structure.
The use of osmolytes or chaperones to stabilize proteins/peptides that misfold in neurodegenerative diseases is an attractive concept for drug development. We have investigated the role of a series of small carbohydrates for protection of the natively structured Alzheimer's amyloid-beta peptides (Abeta). Using circular dichroism spectroscopy to follow the beta-structural transitions and electron microscopy to examine tertiary structural characteristics, we demonstrate that the hydrogen bonding capacity of the carbohydrate determines the inhibition or promotion of fibrillogenesis. Three sugar molecules that vary only in their distribution of potential H-bonding partners promote various structural changes in Abeta. Two of these sugar molecules are excluded from Abeta during aggregation and promote mature fibre growth, while the other binds Abeta promoting nucleation and the accumulation of protofibrils. Our studies suggest that utilization of a combinatorial strategy to alter H-bonding capacity across a simple carbohydrate molecule may represent a novel drug design strategy.
Fung
Justin
J
Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ont., M5S 3H2, Canada.
Darabie
Audrey A
AA
McLaurin
Joanne
J
D016229:Amyloid beta-Peptides / Q000032:analysis / Q000737:chemistry* / Q000648:ultrastructure*; D002942:Circular Dichroism; D003461:Crystallography / Q000379:methods; D046911:Macromolecular Substances / Q000032:analysis / Q000737:chemistry; D008855:Microscopy, Electron, Scanning; D009005:Monosaccharides / Q000032:analysis / Q000737:chemistry*; D010446:Peptide Fragments / Q000032:analysis / Q000737:chemistry* / Q000648:ultrastructure*; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013395:Sucrose / Q000032:analysis / Q000737:chemistry*
D016229:Amyloid beta-Peptides; D046911:Macromolecular Substances; D009005:Monosaccharides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D013395:Sucrose