title: High-resolution atomic force microscopy of soluble Abeta42 oligomers.
abstract: Soluble oligomers and protofibrils are widely thought to be the toxic forms of the Abeta42 peptide associated with Alzheimer's disease. We have investigated the structure and formation of these assemblies using a new approach in atomic force microscopy (AFM) that yields high-resolution images of hydrated proteins and allows the structure of the smallest molecular weight (MW) oligomers to be observed and characterized. AFM images of monomers, dimers and other low MW oligomers at early incubation times (< 1h) are consistent with a hairpin structure for the monomeric Abeta42 peptide. The low MW oligomers are relatively compact and have significant order. The most constant dimension of these oligomers is their height (approximately 1-3 nm) above the mica surface; their lateral dimensions (width and length) vary between 5 nm and 10nm. Flat nascent protofibrils with lengths of over 40 nm are observed at short incubation times (< or = 3h); their lateral dimensions of 6-8 nm are consistent with a mass-per-length of 9 kDa/nm previously predicted for the elementary fibril subunit. High MW oligomers with lateral dimensions of 15-25 nm and heights ranging from 2-8 nm are common at high concentrations of Abeta. We show that an inhibitor designed to block the sheet-to-sheet packing in Abeta fibrils is able to cap the heights of these oligomers at approximately 4 nm. The observation of fine structure in the high MW oligomers suggests that they are able to nucleate fibril formation. AFM images obtained as a function of incubation time reveal a sequence of assembly from monomers to soluble oligomers and protofibrils.
authors.affiliation: LifeAFM, Inc., 10 Rosita Lane, Port Jefferson, NY 11777, USA. mastrang@lifeafm.com
authors.forename: Iris A
authors.initials: IA
authors.lastname: Mastrangelo
authors.forename: Mahiuddin
authors.initials: M
authors.lastname: Ahmed
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sato
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Chengpu
authors.initials: C
authors.lastname: Wang
authors.forename: Paul
authors.initials: P
authors.lastname: Hough
authors.forename: Steven O
authors.initials: SO
authors.lastname: Smith
mesh_terms: D000682:Amyloid / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000648:ultrastructure*; D004247:DNA / Q000737:chemistry; D018625:Microscopy, Atomic Force; D008954:Models, Biological; D008970:Molecular Weight; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000648:ultrastructure*; D010455:Peptides / Q000737:chemistry; D020836:Protein Structure, Quaternary; D012995:Solubility; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D010455:Peptides; C075222:amyloid beta-protein (1-42); D004247:DNA