Triptolide induces the secretion of insulin, through which it alleviates the tauopathies of Alzheimer's disease via inhibiting the phosphorylation of tau.

Triptolide (TP) has shown its therapeutic effects on Alzheimer's disease (AD) via decreasing the overloading of β-amyloid protein (Aβ). However, the roles and mechanisms of TP in the pathogenesis of tau have not been revealed until now. To this end, the current study aimed to assess the effects of TP on AD via tau-associated mechanisms. In detail, TP treatment decreases the phosphorylation of tau, which results in attenuating the cognitive decline of PS19 mice. In the mechanisms, we found that TP treatment elevates the levels of insulin, which lowers the blood glucose, leading to superior performance in the glucose tolerance test, inhibition of AMP-activated protein kinase (AMPK), and the change of serum triglycerides and cholesterol. The in vitro studies demonstrating that TP increases insulin production via cAMP-response element binding protein (CREB)- and pancreatic-duodenal homeobox factor 1 (PDX-1)-dependent mechanisms in MIN6 cells further supported the in vivo findings. By enhancing insulin production, TP upregulates protein O-GlcNAc modification and inhibits Ca/calmodulin-dependent protein kinase 2 (CaMK2) activity to reduce tau phosphorylation in both in vivo and in vitro experiments. Additionally, metabolic changes decrease the activity of the CCAAT/enhancer binding protein beta (C/EBPβ)/asparagine endopeptidase (AEP) signaling pathway, significantly reducing the associated neuroinflammation. Guided by these mechanisms, TP shows inhibitory effects on tau phosphorylation via an insulin secretion-dependent pathway.