GSK3: a key target for the development of novel treatments for type 2 diabetes mellitus and Alzheimer disease

Abstract As a constitutively active kinase, glycogen synthase kinase 3 (GSK3) is a kinase which regulates body metabolism by phosphorylation of glycogen synthase (GS) and other substrates. Considerable evidence suggests that GSK3 is involved in the common pathology underlying Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM). The overexpression or overactivation of GSK3 could induce a series of pathological changes, most of which are hallmarks of AD and T2DM. Therefore, GSK3 could be a novel target to treat these two age-dependent diseases. The inhibition of this kinase can prevent the aggregation of β-amyloid (Aβ) and hyperphosphorylation of tau protein. GSK3 inhibition can also be a promising strategy to ameliorate neurodegenerative developments. Its potential association with memory formation has been shown in electrophysiological and behavioral experiments. The neuroprotective effects of novel drugs developed to treat T2DM, glucagon-like peptide 1 (GLP-1) and its long-lasting analogs, have a possible link to GSK3 modification. Recent investigations of the interaction between the phosphatidylinositol 3 kinase (PI3K) signaling pathway and the protective effect of novel GPL-1 receptor agonist geniposide on PC12 cells support this theory.