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

AbstractPolymerization of the amyloid β-peptide (Aβ) has been identified as a major feature of the pathogenesis of Alzheimer’s disease (AD). Inhibition of the formation of these toxic polymers of Aβ has thus emerged as an approach to developing therapeutics for AD. Techniques for studying Aβ polymerization include the use of fibril nucleation and extension assays in a variety of formats. Detection of polymeric forms of Aβ 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 Aβ 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 Aβ polymers. These compounds include dyes such as Congo Red, the antibiotic rifampicin, the anthracycline 4′-iodo-4′-deoxydoxorubicin, and a large variety of Aβ-derived peptides and modified peptides, among other reported inhibitors