Recent developments in the chemical biology of amyloid- oligomer targeting

Aggregation of amyloid-beta (A beta) peptides is characteristic of Alzheimer's disease (AD), which is the most common neurodegenerative disorder. Increasing evidence shows that A beta oligomers, the intermediates during aggregation, rather than the fully mature fibrils are the most toxic species of A beta and the key contributors to neurodegeneration. A beta oligomers have been considered as both biomarkers and drug targets for the diagnosis and treatment of AD. However, the high heterogeneity and metastability of oligomers make it difficult to determine their exact pathogenic mechanisms. Recent developments in A beta oligomer-targeting agents and techniques have provided great opportunities for overcoming the existing limitations. This review introduces the formation, structure, and toxicity of A beta oligomers and categorizes the A beta oligomer-targeting agents based on their chemical biological applications, including recognition and detection of A beta oligomers for diagnosis, intervention of A beta oligomerization for treatment, and stabilization of A beta oligomers for pathogenic studies. The design strategies and working mechanisms of the representative examples published in the past five years are highlighted. Finally, future development directions and challenges of A beta oligomer targeting are tentatively proposed.