Nonenzymatic function of DPP4 promotes diabetes-associated cognitive dysfunction through IGF-2R/PKA/SP1/ERp29/IP3R2 pathway-mediated impairment of Treg function and M1 microglia polarization

Impairment of regulatory T (Treg) cells function is implicated in the pathogenesis of immune imbalance-mediated cognitive impairment. A complete understanding of whether and how this imbalance affect cognitive function in type 2 diabetes is lacking, and the driver affecting this imbalance remains unknown.We examined the impact of enzymatic and non-enzymatic function of DPP4 on Treg cell impairment, microglia polarization and diabetes-associated cognitive defects and identified its underlying mechanism in type 2 diabetic patients with cognitive impairment and in db/db mice.We report that DPP4 binds to IGF2-R on Treg cell surface and activates PKA/SP1 signaling, which upregulate ERp29 expression and promote its binding to IP3R2, thereby inhibiting IP3R2 degradation and promoting mitochondria-associated ER membrane formation and mitochondria calcium overload in Tregs. This, in turn, impairs Tregs function and polarizes microglia toward a pro-inflammatory phenotype in the hippocampus and finally leads to neuroinflammation and cognitive impairment in type 2 diabetes. Importantly, inhibiting DPP4 enzymatic activity in type 2 diabetic patients or mutating DPP4 enzymatic active site in db/db mice did not reverse these changes. However, IGF-2R knockdown or blockade ameliorated these effects both in vivo and in vitro.These findings highlight the nonenzymatic role of DPP4 in impairing Tregs function, which may facilitate the design of novel immunotherapies for diabetes-associated cognitive impairment.