Navigating the GSK-3β inhibitors as versatile multi-target drug ligands in Alzheimer’s disease intervention – A comprehensive review

Alzheimer's disease (AD) remains a significant global health challenge, necessitating the exploration of novel therapeutic strategies. AD is a neurodegenerative disease characterized by the formation of amyloid-β (Aβ) plaques and neurofibrillary tangles composed of tau protein. It is stated to be a cause of multiple mechanistic pathways and biochemical events, and hence, targeting only one mechanism at a time cannot suffice for all-round therapy. A multi-target drug ligand strategy can thus be employed in such a setting to modulate multiple drug targets simultaneously. Glycogen synthase kinase-3β (GSK-3β) is an enzyme involved in tau hyperphosphorylation, neuroinflammation, maintaining neuronal plasticity, and various cell processes. Thus, inhibiting GSK-3β itself may help in the control of some of the key factors stated to be responsible for Alzheimer's disease pathophysiology. This review comprehensively evaluates the potential of GSK-3β inhibitors as multi-target drug ligands in AD therapeutics. We discuss the molecular mechanisms of GSK-3β in AD pathology and review the preclinical and clinical evidence supporting the efficacy of GSK-3β inhibitors in ameliorating cognitive decline and pathological hallmarks of AD. Furthermore, we explore the challenges associated with targeting GSK-3β, such as selectivity, blood–brain barrier penetration, and adverse effects. Additionally, we highlight recent advances in the development of novel GSK-3β inhibitors with improved pharmacokinetic properties and multitargeting capabilities. Finally, we discuss the future directions and potential clinical implications of GSK-3β inhibitors as multi-target drug ligands in the complex landscape of AD therapeutics.