Approaches to discovery and characterization of inhibitors of amyloid β-peptide polymerization

Polymerization of the amyloid beta-peptide (A beta) has been identified as a major feature of the pathogenesis of Alzheimer's disease (AD). Inhibition of the formation of these toxic polymers of A beta has thus emerged as an approach to developing therapeutics for AD. Techniques for studying A beta polymerization include the use of fibril nucleation and extension assays in a variety of formats. Detection of polymeric forms of A beta has been achieved using turbidity, dye binding, light scattering and toxicity among other methods. Direct and indirect methods have been described for the measurement of binding affinities for A beta fibrils. Imaging techniques include electron microscopy, X-ray diffraction and atomic force microscopy. These techniques have been used to characterize different classes of compounds that inhibit the formation of A beta polymers. These compounds include dyes such as Congo Red, the antibiotic rifampicin, the anthracycline 4'-iodo-4'-deoxydoxorubicin, and a large variety of A beta-derived peptides and modified peptides, among other reported inhibitors. (C) 2000 Elsevier Science B.V. All rights reserved.