Conformation-dependent anti-amyloid oligomer antibodies

Rakez Kayed, Charles G Glabe
Methods in Enzymology 2006, 413: 326-44
Although abundant evidence suggests that amyloid accumulation plays a significant role in the pathogenesis of degenerative disease, the mechanism of amyloid formation and toxicity remains elusive. Early hypotheses for disease pathogenesis proposed that large amyloid deposits, which are composed primarily of 6-10-nm mature amyloid fibrils, were the primary causative agent in pathogenesis, but this hypothesis required modification to consider the central role of oligomers or aggregation intermediates, because the accumulation of these large aggregates does not correlate well with pathogenesis. Recent evidence supports the hypothesis that small soluble aggregates representing intermediates in the fibril assembly process may represent the primary culprits in a variety of amyloid-related degenerative diseases. Investigating the role of soluble amyloid oligomers in pathogenesis presents a problem for distinguishing these aggregates from the mature fibrils, soluble monomer, and natively folded precursor proteins, especially in vivo and in complex mixtures. Recently, we generated a conformation-specific antibody that recognizes soluble oligomers from many types of amyloid proteins, regardless of sequence. These results indicate that soluble oligomers have a common, generic structure that is distinct from both fibrils and low-molecular-weight soluble monomer/dimer. Conformation-dependent, oligomer-specific antibodies represent powerful tools for understanding the role of oligomers in pathogenesis. The purpose of this chapter is to review the methods for the production, characterization, and application of this antibody to understanding the contribution of amyloid oligomers to the disease process.

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