ArticleiScience2023
Non-canonical function of DPP4 promotes cognitive impairment through ERp29-associated mitochondrial calcium overload in diabetes.
Article in iScience, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers, 1 of them a synthesis that pooled it.
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Who cites it
9 citing papers in PubMed, 1 synthesis or guideline pooled it, 17 citations in OpenAlex.
- Dipeptidyl peptidase-4 inhibitors alleviate cognitive dysfunction in type 2 diabetes mellitus.Lipids in health and disease · 2023Pooled it
- The Potential Roles of Oral Hypoglycemic Agents to Modulate Mitochondrial Function in Type 1 Diabetes Mellitus: A Scoping Review.Life (Basel, Switzerland) · 2026Review
- Sitagliptin Modulates Functional and Phenotypic Properties of Human Neutrophils Under Normal- and High-Glucose Conditions In Vitro.Molecules (Basel, Switzerland) · 2026Article
- Trelagliptin Ameliorates Memory Decline in Diabetic Rats through the AMPK/AKT/GSK-3β Pathway in the Cerebral Cortex.ACS omega · 2025Article
- Phosphatidate phosphatase Lipin1 alters mitochondria-associated endoplasmic reticulum membranes (MAMs) homeostasis: effects which contribute to the development of diabetic encephalopathy.Journal of neuroinflammation · 2025Article
- Endothelial MICU1 protects against vascular inflammation and atherosclerosis by inhibiting mitochondrial calcium uptake.The Journal of clinical investigation · 2025Article
- Asymmetrical distribution of supports affect pea plants movement and shape: Evidence of quantity discrimination?PloS one · 2025Article
- A Facile Method for Screening DPP IV Inhibitors in Living Cell System Based on Enzyme Activity Probe.Journal of analytical methods in chemistry · 2025Article
- O-GlcNAcylation of circadian clock protein Bmal1 impairs cognitive function in diabetic mice.The EMBO journal · 2024Article
Corrections and comments
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Authors and funding
10 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
DPP4 has been shown to induce diabetes-associated mitochondrial dysfunction and cognitive impairment through its non-canonical function. Here, we report that enhanced DPP4 expression in diabetes contributes to IP3R2-mediated mitochondria-associated ER membrane (MAM) formation, mitochondria calcium overload, and cognitive impairment, and its knockdown showed opposite effects. Mechanistically, DPP4 binds to PAR2 in hippocampal neurons and activates ERK1/2/CEBPB signaling, which upregulates ERp29 expression and promotes its binding to IP3R2, thereby inhibiting IP3R2 degradation and promoting MAM formation, mitochondria calcium overload, and cognitive impairment. Meanwhile, targeting DPP4-mediated PAR2/ERK1/2/CEBPB/ERp29 signaling achieved satisfactory therapeutic effects on MAM formation, mitochondria calcium overload, and cognitive impairment. Notably, DPP4 activates this pathway in an enzymatic activity-independent manner, suggesting the non-canonical role of DPP4 in the pathogenesis of mitochondria calcium overload and cognitive impairment in diabetes. Together, these results identify DPP4-mediated PAR2/ERK1/2/CEBPB/ERp29 signaling as a promising therapeutic target for the treatment of cognitive impairment in type 2 diabetes.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.