Modulators of Amyloid β-Protein (Aβ) Self-Assembly

Amyloid β-protein (Aβ) is a small, natively unstructured protein with unknown physiological function. In Alzheimer's disease (AD), Aβ self-assembles into metastable, toxic oligomers that injure neurons and synapses, disrupt neuronal communication, and cause gradual neurodegeneration in susceptible brain areas, predominantly those responsible for memory and cognitive function. Aβ oligomers continue to self-associate with other Aβ monomers and oligomers into growing aggregates that in many cases adopt a typical fibrillar structure, characteristic of amyloid. This structure is found in dense neuritic plaques, which are one of the pathological hallmarks of AD and were thought to cause the disease before the realization that the elusive oligomers were the most likely culprits. Although amyloid fibrils no longer are considered the cause of AD, the amyloid often serves as a convenient surrogate for evaluating the effect of potential AD therapies because the oligomers are difficult to measure and study. Due to the centrality of Aβ assemblies in AD, numerous attempts have been made to develop strategies that would disrupt the formation of these toxic pathogens, promote their clearance, or otherwise prevent their harmful effects. The most advanced strategy has been immunotherapy targeting Aβ. Despite high initial hopes and several high-profile clinical trials, this strategy has not led to successful therapy. An alternative strategy is to use small molecules, including peptides, peptidomimetics, natural products, or synthetic organic compounds. We dedicate this chapter to the latter strategy and review its rationale, caveats, and progress in recent years.