Article

Structural characterization of a soluble amyloid beta-peptide oligomer.

Pharmaceutical Discovery Division, GPRD, Abbott Laboratories, Abbott Park, Illinois 60064-6098, USA.
Biochemistry (impact factor: 3.42). 03/2009; 48(9):1870-7. DOI:10.1021/bi802046n pp.1870-7
Source: PubMed

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.

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Keywords

Abeta preglobulomer
 
Alzheimer's disease
 
Alzheimer's patients
 
amyloid beta-peptides
 
antiparallel beta-sheet structure
 
disease progression
 
fibrils
 
homogeneous
 
Long-lived soluble forms
 
mixed parallel
 
parallel beta-sheets
 
parent wt globulomer
 
presence correlates
 
small amounts
 
soluble Abeta globulomer
 
Soluble forms
 
soluble oligomeric assemblies
 
soluble oligomers
 
structural data
 
synaptic activity