Structural characterization of a soluble amyloid β-peptide oligomer

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder that is linked to the presence of amyloid β-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 β-peptides. Using NMR, we have characterized soluble oligomers of Aβ preglobulomer and globulomer that are stable and alter synaptic activity. The NMR data indicate that these soluble forms have a mixed parallel and antiparallel β-sheet structure that is different from fibrils which contain only parallel β-sheets. Using the structural data, we engineered a disulfide bond into the soluble Aβ 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. © 2009 American Chemical Society.