Reimagining GSK-3β Therapeutics in Alzheimer's Disease: From Inhibition to Activity Normalization and Targeted Degradation.

Glycogen Synthase Kinase-3β (GSK-3β) acts as a critical pathogenic amplifier in Alzheimer’s disease (AD), linking and intensifying various degenerative processes such as amyloid-β formation, tau hyperphosphorylation, and neuroinflammation. Rather than serving solely as an upstream trigger, the hyperactivity of GSK-3β interacts with other dysregulated kinases, including CDK5, DYRK1A, and MARKs, to worsen neurodegeneration. This collaboration leads to increased neuronal cell death and cognitive decline in AD patients. However, the clinical translation of conventional GSK-3β inhibitors has been thwarted by a fundamental paradox: complete enzymatic blockade induces Wnt-mediated toxicity, while partial inhibition often fails due to compensatory feedback. This review argues for a paradigm shift: from broad kinase suppression to precise activity normalization. We critically analyze the translational failures of catalytic inhibitors, then examine emerging strategies capable of restoring physiological kinase homeostasis. Foremost among these are brain-penetrant Proteolysis-Targeting Chimeras (PROTACs), which eliminate both the catalytic and non-catalytic (scaffold) functions of GSK-3β through targeted proteasomal degradation, thereby addressing pathological activities that conventional inhibitors leave intact. Furthermore, we explore the synergistic potential of multi-target-directed ligands (MTDLs) and indirect modulation via the gut-brain axis to widen the therapeutic window. By recalibrating rather than silencing GSK-3β, this framework outlines a mechanistically grounded roadmap for achieving safe and effective disease modification in AD, moving this central kinase from an undruggable liability to a central component of future therapeutic strategies.