The heightened pTau (Ser199/202) immunoreactivity observed in 3xTg-AD mice suggests that nondependent alcohol use may produce enduring changes in the functional effects of GSK3 that underly neural pathology. Moreover, GSK3 may represent a therapeutic target for neurodegeneration associated with alcohol use or abuse. A growing literature indicates that pharmacological or genetic inhibition of GSK3 blocks cleavage of APP, which reduces Aβ deposits and restores hippocampal-dependent spatial memory (water maze) in mice (King et al., 2014; Ly et al., 2013; Rockenstein et al., 2007). Similarly, chronic GSK3β inhibition reduces Tau phosphorylation and improves memory in 3xTg-AD mice (Huang et al., 2019). Although GSK3 inhibitors have produced mixed results in clinical trials, selective non-ATP competitive compounds are well-tolerated in vivo and serve as useful experimental tools to probe mechanism of action and may have therapeutic efficacy under specific pathological conditions. For example, non-ATP competitive TDZD derivative tideglusib (200mg/kg, p.o. for 3months) reduces AD-like pathology in mice including decreased Tau phosphorylation and Aβ deposition in the entorhinal cortex and HPC (CA1) with associated prevention of memory deficits in the Morris Water Maze (Sereno et al., 2009). More research is needed to determine if GSK3 inhibition modulates Tau pathology seen following alcohol exposure.
