title: Structural differences between Abeta(1-40) intermediate oligomers and fibrils elucidated by proteolytic fragmentation and hydrogen/deuterium exchange.
abstract: The aggregation of amyloid-beta protein (Abeta) in vivo is a critical pathological event in Alzheimer's disease. Although more and more evidence shows that the intermediate oligomers are the primary neurotoxic species in Alzheimer's disease, the particular structural features responsible for the toxicity of these intermediates are poorly understood. We measured the peptide level solvent accessibility of multiple Abeta(1-40) aggregated states using hydrogen exchange detected by mass spectrometry. A gradual reduction in solvent accessibility, spreading from the C-terminal region to the N-terminal region was observed with ever more aggregated states of Abeta peptide. The observed hydrogen exchange protection begins with reporter peptides 20-34 and 35-40 in low molecular weight oligomers found in fresh samples and culminates with increasing solvent protection of reporter peptide 1-16 in long time aged fibrillar species. The more solvent exposed structure of intermediate oligomers in the N-termini relative to well-developed fibrils provides a novel explanation for the structure-dependent neurotoxicity of soluble oligomers reported previously.
authors.affiliation: Department of Chemical Engineering, University of Virginia, Charlottesville, Virginia 22904, USA.
authors.forename: Aming
authors.initials: A
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Qi
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Good
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Fernandez
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry* / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D016477:Artifacts; D041961:Deuterium Exchange Measurement; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D008970:Molecular Weight; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism*; D012997:Solvents / Q000378:metabolism
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D012997:Solvents; C078592:amyloid beta-protein (1-40)