Monitoring and Targeting the Initial Dimerization Stage of Amyloid Self-Assembly

Amyloid deposits are pathological hallmark of a large group of human degenerative disorders of unrelated etiologies. While accumulating evidence suggests that early oligomers may account for tissue degeneration, most detection tools do not allow the monitoring of early association events. Here we exploit bimolecular fluorescence complementation analysis to detect and quantify the dimerization of three major amyloidogenic polypeptides; islet amyloid polypeptide, β‐amyloid and α‐synuclein. The constructed systems provided direct visualization of protein‐protein interactions in which only assembled dimers display strong fluorescent signal. Potential inhibitors that interfere with the initial intermolecular interactions of islet amyloid polypeptide were further identified using this system. Moreover, the identified compounds were able to inhibit the aggregation and cytotoxicity of islet amyloid polypeptide, demonstrating the importance of targeting amyloid dimer formation for future drug development. A bimolecular fluorescence complementation assay was employed to detect, monitor, and quantify the initial intermolecular interactions that lead to the amyloid self‐assembly cascade. Several compounds that interfere with the dimerization process of the type 2 diabetes‐associated islet amyloid polypeptide were identified. These compounds inhibit aggregation, shift the conformers equilibrium towards monomeric species, and ameliorate islet amyloid polypeptide cytotoxicity.