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.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

The influencing factors and functions of DNA G-quadruplexes.

G-quadruplexes form folded structures because of tandem repeats of guanine sequences in DNA or RNA. They adopt a variety of conformations, depending on many factors, including the type of loops and cations, the nucleotide strand number, and the main strand polarity of the G-quadruplex. Meanwhile, the different conformations of G-quadruplexes have certain influences on their biological functions, such as the inhibition of transcription, translation, and DNA replication. In addition, G-quadruplex binding proteins also affect the structure and function of G-quadruplexes. Some chemically synthesized G-quadruplex sequences have been shown to have biological activities. For example, bimolecular G-quadruplexes of AS1411 act as targets of exogenous drugs that inhibit the proliferation of malignant tumours. G-quadruplexes are also used as vehicles to deliver nanoparticles. Thus, it is important to identify the factors that influence G-quadruplex structures and maintain the stability of G-quadruplexes. Herein, we mainly discuss the factors influencing G-quadruplexes and the synthetic G-quadruplex, AS1411. SIGNIFICANCE OF THE STUDY: This review summarizes the factors that influence G-quadruplexes and the functions of the synthetic G-quadruplex, AS1411. It also discusses the use of G-quadruplexes for drug delivery in tumour therapy.