Glycogen Synthase Kinase 3ß: A New Gold Rush in Anti-Alzheimer's Disease Multitarget Drug Discovery?

Alzheimer's disease (AD), like other multifactorial diseases, is the result of a systemic breakdown of different physiological networks. As result, several lines of evidence suggest that it could be more efficiently tackled by molecules directed toward different dysregulated biochemical targets or pathways. In this context, the selection of targets to which the new molecules will be directed is crucial. For years, the design of such multitarget-directed ligands (MTDLs) has been based on the selection of main targets involved in the "cholinergic" and the "ß-amyloid" hypothesis. Recently, there have been some reports on MTDLs targeting the glycogen synthase kinase 3ß (GSK-3ß) enzyme, due to its appealing properties. Indeed, this enzyme is involved in tau hyperphosphorylation, controls a multitude of CNS-specific signaling pathways, and establishes strict connections with several factors implicated in AD pathogenesis. In the present Miniperspective, we will discuss the reasons behind the development of GSK-3ß-directed MTDLs and highlight some of the recent efforts to obtain these new classes of MTDLs as potential disease-modifying agents.