title: Resolution of oligomeric species during the aggregation of Aβ1-40 using (19)F NMR.
abstract: In the commonly used nucleation-dependent model of protein aggregation, aggregation proceeds only after a lag phase in which the concentration of energetically unfavorable nuclei reaches a critical value. The formation of oligomeric species prior to aggregation can be difficult to detect by current spectroscopic techniques. By using real-time (19)F NMR along with other techniques, we are able to show that multiple oligomeric species can be detected during the lag phase of Aβ1-40 fiber formation, consistent with a complex mechanism of aggregation. At least six types of oligomers can be detected by (19)F NMR. These include the reversible formation of large β-sheet oligomer immediately after solubilization at high peptide concentration, a small oligomer that forms transiently during the early stages of the lag phase, and four spectroscopically distinct forms of oligomers with molecular weights between ∼30 and 100 kDa that appear during the later stages of aggregation. The ability to resolve individual oligomers and track their formation in real-time should prove fruitful in understanding the aggregation of amyloidogenic proteins and in isolating potentially toxic nonamyloid oligomers.
authors: Department of Chemistry, Materials Science and Biomedical Engineering, University of Michigan, Ann Arbor, Michigan 48109, United States.
authors: Yuta
authors: Y
authors: Suzuki
authors: Jeffrey R
authors: JR
authors: Brender
authors: Molly T
authors: MT
authors: Soper
authors: Janarthanan
authors: J
authors: Krishnamoorthy
authors: Yunlong
authors: Y
authors: Zhou
authors: Brandon T
authors: BT
authors: Ruotolo
authors: Nicholas A
authors: NA
authors: Kotov
authors: Ayyalusamy
authors: A
authors: Ramamoorthy
authors: E Neil G
authors: EN
authors: Marsh
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000648:ultrastructure; D002942:Circular Dichroism; D006801:Humans; D008715:Methionine / Q000031:analogs & derivatives / Q000737:chemistry; D018625:Microscopy, Atomic Force; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000737:chemistry* / Q000648:ultrastructure; D017433:Protein Structure, Secondary; D012995:Solubility
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C037646:trifluoromethionine; D008715:Methionine