Light‐controlled molecular tweezers capture specific amyloid oligomers

Abstract Amyloid‐β peptide (Aβ) oligomers, characteristic symptom of Alzheimer's disease (AD), have been identified as the most neurotoxic species and significant contributors to neurodegeneration in AD. However, due to their transient and heterogeneous nature, the high‐resolution structures and exact pathogenic processes of Aβ oligomers are currently unknown. Using light‐controlled molecular tweezers (LMTs), we describe a method for precisely capturing specific Aβ oligomers produced from synthetic Aβ and AD animal models. Light irradiation can activate LMTs, which are composed of two Aβ‐targeting pentapeptides (KLVFF) motifs and a rigid azobenzene (azo) derivative, to form a tweezer‐like cis configuration that preferentially binds to specific oligomers matching the space of the tweezers via multivalent interactions of KLVFF motifs with the oligomers. Surprisingly, cis‐LMTs can immobilize the captured oligomers in transgenic Caenorhabditis elegans under light irradiation. The LMTs may serve as spatiotemporally controllable molecular tools to extract specific native oligomers for the structure and function studies via reversible photoisomerization, which would improve the understanding of the toxic mechanisms of Aβ oligomers and development of oligomer‐targeted diagnosis and therapy.