Discovery of fluorescent and theranostic probes for glycogen synthase kinase-3β in living cells and brain tissues: Detection and imaging in models of Alzheimer's disease

Abstract

Alzheimer's disease (AD) represents a progressive neurodegenerative disorder marked by complex pathologies. Glycogen synthase kinase-3β (GSK-3β) plays a pivotal role in AD pathogenesis, influencing key pathological processes such as hyperphosphorylation of tau and production of amyloid-beta. However, current methods for detecting GSK-3β in living cells and tissues are limited in sensitivity and real-time tracking. Herein, we reported a series of environment-sensitive fluorescent probes to detect GSK-3β in both living cells and brain slices. These probes exhibit fluorescence upon the binding of GSK-3β, providing high sensitivity and selectivity with minimal background interference. Compound 10c was further validated in an AD mouse model with elevated expression of GSK-3β, showing clear imaging in hippocampal regions. Compared to immunofluorescence, compound 10c demonstrated a lower background and faster labeling. In addition, this compound showed neuroprotective effects, supporting its potential as a theranostic tool in AD. These findings provide new tools for investigating the role of GSK-3β in AD and advancing targeted therapies.