In vivo visualization of enantioselective targeting of amyloid and improvement of cognitive function by clickable chiral metallohelices

The pathogenesis of Alzheimer's disease (AD) is closely related to several contributing factors, especially amyloid-beta (A beta) aggregation. Bioorthogonal reactions provide a general, facile, and robust route for the localization and derivatization of A beta-targeted agents. Herein, a pair of chiral alkyne-containing metallohelices (lambda A and & UDelta;A) were demonstrated to enantioselectively target and modulate A beta aggregation, which has been monitored in triple-transgenic AD model mice and proved to improve cognitive function. Compared with its enantiomer & UDelta;A, lambda A performed better in blocking A beta fibrillation, relieving A beta-triggered toxicity, and recovering memory deficits in vivo. Moreover, clickable lambda A could act as a functional module for subsequent visualization and versatile modification of amyloid via bioorthogonal reaction. As a proof-of-concept, thioflavin T, tacrine, and magnetic nanoparticles were conjugated with lambda A to realize A beta photo-oxygenation, acetylcholinesterase inhibition, and A beta clearance, respectively. This proof-of-principle work provided new insights into the biolabeling and bioconjugation of multifunctional metallosupramolecules through click reactions for AD therapy.