ArticleJournal of advanced research2025
Hippocampal dipeptidyl peptidase 9 bidirectionally regulates memory associated with synaptic plasticity.
Article in Journal of advanced research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Neuronal inflammasomes: balancing immunity, neuroinflammation, and homeostasis.Trends in immunology · 2026Review
- Proximity labeling reveals non-catalytic interactions between DPP9 and ubiquitin signaling complexes.Cellular and molecular life sciences : CMLS · 2026Article
- Targeting DPP9 attenuates podocyte injury by regulating NRF2 antioxidant signaling.Frontiers in pharmacology · 2026Article
- A Photocaged N-Phosphonopiperidinone as a Selective Photo-Cleavable DPP8/9 Inhibitor.Chembiochem : a European journal of chemical biology · 2025Article
- The multifunctional regulatory post-proline protease dipeptidyl peptidase 9 and its inhibitors: new opportunities for therapeutics.Cellular and molecular life sciences : CMLS · 2025Review
- Targeting ApoE-KCC2 Signaling Rescues GABAergic Synaptic Dysfunction and Depression-like Behaviors in Mice.Research (Washington, D.C.) · 2025Article
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Authors and funding
8 authors.
Funding
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Abstract
introductionSubtypes of the dipeptidyl peptidase (DPP) family, such as DPP4, are reportedly associated with memory impairment. DPP9 is widely distributed in cells throughout the body, including the brain. However, whether DPP9 regulates memory has not yet been elucidated.
objectivesThis study aimed to elucidate the role of DPP9 in memory, as well as the underlying molecular mechanism.
methodsWe performed immunofluorescence on mouse brains to explore the distribution of DPP9 in different brain regions and used AAV vectors to construct knockdown and overexpression models. The effects of changing DPP9 expression on memory were demonstrated through behavioral experiments. Finally, we used electrophysiology, proteomics and affinity purification mass spectrometry (AP-MS) to study the molecular mechanism by which DPP9 affects memory.
resultsHere, we report that DPP9, which is found almost exclusively in neurons, is expressed and has enzyme activity in many brain regions, especially in the hippocampus. Hippocampal DPP9 expression increases after fear memory formation. Fear memory was impaired by DPP9 knockdown and enhanced by DPP9 protein overexpression in the hippocampus. According to subsequent hippocampal proteomics, multiple pathways, including the peptidase pathway, which can be bidirectionally regulated by DPP9. DPP9 directly interacts with its enzymatic substrate neuropeptide Y (NPY) in neurons. Hippocampal long-term potentiation (LTP) is also bidirectionally regulated by DPP9. Moreover, inhibiting DPP enzyme activity impaired both LTP and memory. In addition, AP-MS revealed that DPP9-interacting proteins are involved in the functions of dendritic spines and axons. By combining AP-MS and proteomics, DPP9 was shown to play a role in regulating actin functions.
conclusionTaken together, our findings reveal that DPP9 affects the CNS not only through enzymatic activity but also through protein-protein interactions. This study provides new insights into the molecular mechanisms of memory and DPP family functions.
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