title: Structural characterization of a soluble amyloid beta-peptide oligomer.
abstract: Alzheimer's disease (AD) is a neurodegenerative disorder that is linked to the presence of amyloid beta-peptides that can form insoluble fibrils or soluble oligomeric assemblies. Soluble forms are present in the brains and tissues of Alzheimer's patients, and their presence correlates with disease progression. Long-lived soluble forms can be generated in vitro by using small amounts of aliphatic hydrocarbon chains of detergents or fatty acids in preparations of amyloid beta-peptides. Using NMR, we have characterized soluble oligomers of Abeta preglobulomer and globulomer that are stable and alter synaptic activity. The NMR data indicate that these soluble forms have a mixed parallel and antiparallel beta-sheet structure that is different from fibrils which contain only parallel beta-sheets. Using the structural data, we engineered a disulfide bond into the soluble Abeta globulomer to give a "new" soluble antigen that is stable, homogeneous, and binds with the same affinity to selective antibodies as the parent wt globulomer.
authors.affiliation: Pharmaceutical Discovery Division, GPRD, Abbott Laboratories, Abbott Park, Illinois 60064-6098, USA.
authors.forename: Liping
authors.initials: L
authors.lastname: Yu
authors.forename: Rohinton
authors.initials: R
authors.lastname: Edalji
authors.forename: John E
authors.initials: JE
authors.lastname: Harlan
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Holzman
authors.forename: Ana Pereda
authors.initials: AP
authors.lastname: Lopez
authors.forename: Boris
authors.initials: B
authors.lastname: Labkovsky
authors.forename: Heinz
authors.initials: H
authors.lastname: Hillen
authors.forename: Stefan
authors.initials: S
authors.lastname: Barghorn
authors.forename: Ulrich
authors.initials: U
authors.lastname: Ebert
authors.forename: Paul L
authors.initials: PL
authors.lastname: Richardson
authors.forename: Laura
authors.initials: L
authors.lastname: Miesbauer
authors.forename: Larry
authors.initials: L
authors.lastname: Solomon
authors.forename: Diane
authors.initials: D
authors.lastname: Bartley
authors.forename: Karl
authors.initials: K
authors.lastname: Walter
authors.forename: Robert W
authors.initials: RW
authors.lastname: Johnson
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Hajduk
authors.forename: Edward T
authors.initials: ET
authors.lastname: Olejniczak
mesh_terms: D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D018625:Microscopy, Atomic Force; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D012995:Solubility
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)