Glycogen Synthase Kinase-3β in Alzheimer's Disease: Targets for Therapy and Imaging

Glycogen synthase kinase-3β (GSK-3β) is a key regulator of the pathogenesis of Alzheimer's disease (AD), capable of simultaneously modulating core pathological processes such as amyloid-β (Aβ) deposition, tau protein hyperphosphorylation, synaptic damage, and neuroinflammation. Therefore, it has become one of the core druggable molecular nodes for AD intervention. This review is mainly divided into two parts. The first part focuses on the GSK-3β inhibitors that have been validated in AD-related cell and animal models. These inhibitors are specifically classified into four categories: metal ion-based compounds, adenosine triphosphate (ATP)-competitive inhibitors, non-ATP-competitive inhibitors, and multi-target inhibitors. The second part focuses on GSK-3β-specific positron emission tomography (PET) radioligands, which can non-invasively monitor GSK-3β enzyme activity in vivo, providing quantitative in vivo molecular imaging tracers for the study of AD pathogenesis and quantitative assessment of treatment effects. This review systematically summarizes GSK-3β-related inhibitors and PET radioligands in AD, thereby providing key references for the rational design of next-generation AD therapeutic drugs and diagnostic agents.