Glycogen synthase kinase-3: the master switch driving neurodegeneration in Alzheimer's disease and Parkinson's disease.

Glycogen synthase kinase-3 (GSK-3) is a critical serine/threonine kinase that plays a central role in regulating various cellular processes. In the nervous system, GSK-3 is particularly implicated in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Recent studies have demonstrated that GSK-3 modulates multiple pathological mechanisms through diverse signaling pathways, including PI3K/Akt and Wnt/β-catenin. These mechanisms involve Tau protein hyperphosphorylation, β-amyloid production and deposition, autophagic dysfunction in neurons, and impaired synaptic plasticity. This review summarizes the biological functions of GSK-3, its signaling mechanisms, and its multifaceted roles in neurodegenerative disease progression. Furthermore, we highlight current therapeutic strategies targeting GSK-3 and recent advances in preclinical studies. In particular, three representative classes of GSK-3 inhibitors-namely allosteric covalent inhibitors, multi-target regulators, and ATP-competitive inhibitors-are discussed with respect to their mechanisms of action and research progress. Summary, GSK-3 represents a central pathological mediator and a promising therapeutic target in neurodegenerative disorders, and targeted modulation of GSK-3 activity may offer a potential disease-modifying approach for future interventions.