Fig. 8

The hypothesized mechanism by which Ex-4 reduces tau hyperphosphorylation via Wnt/β-catenin/NeuroD1 signalling in T2D models. The AD-associated tau hyperphosphorylation in the hippocampus of db/db mice, HF-diabetic mice, and HT22 cells damaged by the high glucose environment was significantly higher than that in normal control. The mechanism in the current study could describe as exendin-4 activated the GLP-1 receptor on the hippocampal membrane, leading to the activation of the cAMP-PKA pathway in the GLP-1 signalling pathway, and PKA could lead to an increase in the level of nonphosphorylated β-catenin, which activated the Wnt/β-catenin signalling. Then, the downstream factor NeuroD1 of this pathway is increased and translocated into the nucleus. NeuroD1 bound to the promoter region of the insulin-encoding gene Ins2, thereby promoting the production and secretion of insulin. The elevated insulin activates the insulin signalling pathway and inhibits the activity of GSK-3β, ultimately reducing the hyperphosphorylation of AD-associated tau proteins regulated by GSK-3β