DPP-4 Inhibitors Suppress Tau Phosphorylation and Promote Neuron Autophagy through the AMPK/mTOR Pathway to Ameliorate Cognitive Dysfunction in Diabetic Mellitus.

Dipeptidyl peptidase-4 (DPP-4) inhibitors have been considered as incretin-based agents that signal through GLP-1R. Our high-throughput RNA sequencing (RNA-seq) and bioinformatics methods indicated that GLP-1R, downregulated in diabetes mellitus (DM), was a potential target of DPP-4 inhibitors, which was further confirmed in DM rats. Thus, this study illuminated the alleviatory mechanism of DPP-4 on cognitive dysfunction in diabetes mellitus (DM), which may be associated with GLP-1R signaling. DM rats were administered with DPP-4 inhibitors, Chloroquine (an autophagy inhibitor), Exendin 9-39 (a GLP-1R antagonist), or Compound C (a specific inhibitor of AMPK). An in vitro model of DM was induced in rat hippocampal neuronal cell line H19-7 by exposure to high glucose (HG) and high fat (HF), followed by treatment with the above inhibitors and antagonists. It was found that cognitive dysfunction was promoted, and LC3 expression was lowered in DM rats by an autophagy inhibitor. The DPP-4 inhibitors decreased cognitive dysfunction, repressed Tau phosphorylation, and enhanced GLP-1R protein level, LC3 expression, and AMPK and mTOR phosphorylation in DM rats, while GLP-1R antagonist, an autophagy inhibitor, or AMPK inhibitor counteracted these effects. Such effects were also observed in HG/HF-induced neurons. In conclusion, our data elucidated the alleviatory mechanism of DPP-4 inhibitors in the cognitive dysfunction of DM rats via the AMPK/mTOR pathway.