2. Academic Validation
  3. Hippocampal dipeptidyl peptidase 9 bidirectionally regulates memory associated with synaptic plasticity

Hippocampal dipeptidyl peptidase 9 bidirectionally regulates memory associated with synaptic plasticity

  • J Adv Res. 2024 Oct 5:S2090-1232(24)00433-8. doi: 10.1016/j.jare.2024.09.031.
Ya-Bo Zhao 1,  Shi-Zhe Wang 2,  Wen-Ting Guo 2,  Le Wang 2,  Xun Tang 1,  Jin-Nan Li 1,  Lin Xu 3,  Qi-Xin Zhou 4
Affiliations

Affiliations

  • 1 Key Laboratory of Animal Models and Human Disease Mechanisms of Yunnan Province, and Laboratory of Learning and Memory, Kunming Institute of Zoology, The Chinese Academy of Sciences (CAS), Kunming 650223, China.
  • 2 Key Laboratory of Animal Models and Human Disease Mechanisms of Yunnan Province, and Laboratory of Learning and Memory, Kunming Institute of Zoology, The Chinese Academy of Sciences (CAS), Kunming 650223, China; University of Chinese Academy of Sciences, Beijing 101408, China.
  • 3 Key Laboratory of Animal Models and Human Disease Mechanisms of Yunnan Province, and Laboratory of Learning and Memory, Kunming Institute of Zoology, The Chinese Academy of Sciences (CAS), Kunming 650223, China; University of Chinese Academy of Sciences, Beijing 101408, China; KIZ-SU Joint Laboratory of Animal Model and Drug Development, China.
  • 4 Key Laboratory of Animal Models and Human Disease Mechanisms of Yunnan Province, and Laboratory of Learning and Memory, Kunming Institute of Zoology, The Chinese Academy of Sciences (CAS), Kunming 650223, China; University of Chinese Academy of Sciences, Beijing 101408, China. Electronic address: qixin_zhou@vip.126.com.
PMID: 39369958 DOI: 10.1016/j.jare.2024.09.031
Abstract

Introduction: Subtypes 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.

Objectives: This study aimed to elucidate the role of DPP9 in memory, as well as the underlying molecular mechanism.

Methods: We 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.

Results: Here, 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.

Conclusion: Taken 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.

Keywords

DPP9; Hippocampus; Learning; Memory; Proteomics.

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