The viruses used in this article from BrainVTA are in the table below

Dipeptidyl peptidase-4 (DPP4) has been proven to exert its functions by both enzymatic and nonenzymatic pathways. The nonenzymatic function of DPP4 in diabetes-associated cognitive impairment remains unexplored. We determined DPP4 protein concentrations or its enzymatic activity in type 2 diabetic patients and db/db mice and tested the impact of the non-enzymatic function of DPP4 on mitochondrial dysfunction and cognitive impairment both in vivo and in vitro. The results show that increased DPP4 activity was an independent risk factor for incident mild cognitive impairment (MCI) in type 2 diabetic patients. In addition, DPP4 was highly expressed in the hippocampus of db/db mice and contributed to mitochondria dysfunction and cognitive impairment. Mechanistically, DPP4 might bind to PAR2 in the hippocampus and trigger GSK-3β activation, which downregulates peroxisome proliferator-activated receptor gamma coactivator 1 alpha expression and leads to mitochondria dysfunction, thereby promoting cognitive impairment in diabetes. Our findings indicate that the nonenzymatic function of DPP4 might promote mitochondrial dysfunction and cognitive impairment in diabetes.

Figure 1. Increased plasma dipeptidyl peptidase-4 (DPP4) activity is an independent risk factor for incident mild cognitive impairment (MCI), and this association is partially mediated by oxidative stress and inflammation.

In this study, the authors explored the nonenzymatic function of DPP4 in diabetes-associated cognitive impairment. The results indicate that the nonenzymatic function of DPP4 might promote mitochondrial dysfunction and cognitive impairment in diabetes, which provides a molecular expla-nation for the nonenzymatic role of DPP4 in the pathogenesis of cognitive impairment in diabetes and highlights the fact that inhibiting enzymatic function of DPP4 alone might not be able to break the link between DPP4 and cognitive impairment in diabetes.

 
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