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

  • Eur J Med Chem. 2025 Jul 5:291:117639. doi: 10.1016/j.ejmech.2025.117639.
Yu Chen  1 ,  Hanyue Dong  1 ,  Xiaoling Huang  1 ,  Lulu Jiang  1 ,  Zixing Jiang  1 ,  Lanqing Li  1 ,  Jinhui Hu  2 ,  Wen-Hua Chen  3
Affiliations
  • 1. Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Pharmacy and Food Engineering, Wuyi University, Jiangmen, 529020, PR China.
  • 2. Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Pharmacy and Food Engineering, Wuyi University, Jiangmen, 529020, PR China. Electronic address: [email protected].
  • 3. Guangdong Provincial Key Laboratory of Large Animal Models for Biomedicine, School of Pharmacy and Food Engineering, Wuyi University, Jiangmen, 529020, PR China. Electronic address: [email protected].
PMID: 40267876 DOI: 10.1016/j.ejmech.2025.117639
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.

Keywords
Brain tissue; Fluorescent probe; GSK-3β; Living cell; Theranostics.
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