Inhibition of Amyloid-β Aggregation in Alzheimer's Disease

The assembly of naturally occurring amyloid peptides into cytotoxic oligomeric and fibrillar aggregates is believed to be a major pathologic event in over 25 human diseases. Blocking of or interfering with the aggregation of amyloid peptides such as amyloid-beta (A beta) using small organic molecules, peptides and peptidomimetics, and nanoparticles that selectively bind or inhibit A beta aggregates is a promising strategy for the development of novel pharmaceutical approaches and agents to treat Alzheimer's disease (AD). In a broad sense, considering many common features in structure, kinetics, and biological activity of amyloid peptides, potent inhibitors and associated inhibition strategies that are developed for targeting A beta aggregation could also be generally applied to other amyloid-forming peptides in protein-aggregation diseases. Due to the complex nature of A beta self-assembly process, increasing knowledge in high-resolution structures of A beta oligomers, atomic-level A beta-inhibitorbinding information, and cost-effective high-throughput screening method will improve our fundamental understanding of amyloid formation and inhibition mechanisms, as well as practical design of pharmaceutical strategies and drugs to treat AD. This review summarizes major findings, recent advances, and future challenges for the development of new A beta-aggregation inhibitors, mainly focusing on three major classes of A beta inhibitors with associated inhibition mechanisms and practical examples.