Manipulating the amyloid-beta aggregation pathway with chemical chaperones.
Amyloid-beta (Abeta) assembly into fibrillar structures is a defining characteristic of Alzheimer's disease that is initiated by a conformational transition from random coil to beta-sheet and a nucleation-dependent aggregation process. We have investigated the role of organic osmolytes as chemical chaperones in the amyloid pathway using glycerol to mimic the effects of naturally occurring molecules. Osmolytes such as the naturally occurring trimethylamine N-oxide and glycerol correct folding defects by preferentially hydrating partially denatured proteins and entropically stabilize native conformations and polymeric states. Trimethylamine N-oxide and glycerol were found to rapidly accelerate the Abeta random coil-to-beta-sheet conformational change necessary for fiber formation. This was accompanied by an immediate conversion of amorphous unstructured aggregates into uniform globular and possibly nucleating structures. Osmolyte-facilitated changes in Abeta hydration also affected the final stages of amyloid formation and mediated transition from the protofibrils to mature fibers that are observed in vivo. These findings suggest that hydration forces can be used to control fibril assembly and may have implications for the accumulation of Abeta within intracellular compartments such as the endoplasmic reticulum and in vitro modeling of the amyloid pathway.
Yang
D S
DS
Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario M5S 3H2, Canada.
Yip
C M
CM
Huang
T H
TH
Chakrabartty
A
A
Fraser
P E
PE
D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000648:ultrastructure; D002942:Circular Dichroism; D005456:Fluorescent Dyes / Q000737:chemistry; D005990:Glycerol / Q000494:pharmacology; D006801:Humans; D008744:Methylamines / Q000494:pharmacology; D018625:Microscopy, Atomic Force; D008854:Microscopy, Electron; D018832:Molecular Chaperones / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry* / Q000648:ultrastructure; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D012995:Solubility; D013050:Spectrometry, Fluorescence
D016229:Amyloid beta-Peptides; D005456:Fluorescent Dyes; D008744:Methylamines; D018832:Molecular Chaperones; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C005855:trimethyloxamine; D005990:Glycerol