Structural Characterization of a Soluble Amyloid β-Peptide Oligomer

作者：Liping Yu, Rohinton Edalji, John E. Harlan, Thomas F. Holzman, Ana Rodríguez López, Boris Labkovsky, Heinz Hillen, Stefan Barghorn, Ulrich Ebert, Paul L. Richardson, Laura R. Miesbauer, Larry R. Solomon, Diane M. Bartley, Karl A. Walter, Robert W. Johnson, Philip J. Hajduk, Edward T. Olejniczak · 发表于：Biochemistry · 年份：2009 · DOI：10.1021/bi802046n · 被引用次数：356 · 研究领域：Alzheimer's disease research and treatments、Supramolecular Self-Assembly in Materials、Graph theory and applications

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.