Structural characterization of a soluble amyloid beta-peptide oligomer.
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.
Yu
Liping
L
Pharmaceutical Discovery Division, GPRD, Abbott Laboratories, Abbott Park, Illinois 60064-6098, USA.
Edalji
Rohinton
R
Harlan
John E
JE
Holzman
Thomas F
TF
Lopez
Ana Pereda
AP
Labkovsky
Boris
B
Hillen
Heinz
H
Barghorn
Stefan
S
Ebert
Ulrich
U
Richardson
Paul L
PL
Miesbauer
Laura
L
Solomon
Larry
L
Bartley
Diane
D
Walter
Karl
K
Johnson
Robert W
RW
Hajduk
Philip J
PJ
Olejniczak
Edward T
ET
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
D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)