Dexter Energy Transfer Photocatalytic Microdissection of Amyloid Plaques in Alzheimer’s Disease

Amyloid plaque is a pathological hallmark in Alzheimer's disease (AD) brain with its composition associated with disease etiology. Here, we report a photocatalyst, namely, AmyCAT, that selectively binds to amyloid fibrils in AD brain tissues and undergoes Dexter energy transfer (DET) to catalyze carbene production for amyloid proximity labeling. First, we designed the AmyCAT photocatalyst to universally bind different types of amyloids. Second, we energetically match the DET effect in a 12 × 4 photocatalyst-substrate array to activate the diazo substrate into reactive carbene species by visible green light (530-545 nm). Further, we demonstrate that the optimal AmyCAT probe catalyzes pan-amyloid protein labeling with a 30-fold selectivity over folded counterparts. Mechanistic studies confirm that the photocatalytic labeling is indeed via the DET process, which tailors the proximity effect for spatially confined amyloid labeling. Finally, we employ the AmyCAT photocatalyst to label, enrich, and profile amyloid plaques in AD brain tissues, identifying key proteins and pathways associated with AD pathological deposition and etiology. The small-molecule-based strategy reported herein dispenses with the antibody, genetic modification, or microscopes to dissect and profile amyloid deposits from AD tissues.