VAMP2-mediated PPAR signaling modulates mitophagy and inflammatory responses in Mg2+-free induced HT22 neuronal cells
- 1Department of Pediatrics, Henan Provincial People’s Hospital, No.7, Weiwu Road, Jinshui District, Zhengzhou City, Henan Province 450000 People’s Republic of China
Abstract
Objective: To explore the neuroprotective effects and molecular mechanism of the VAMP2-mediated PPAR signaling pathway on neuronal mitophagy using an in vitro seizure-like injury model.
Methods: A seizure model was established by culturing mouse hippocampal HT22 cells in Mg2+-free medium. siRNA-mediated gene knockdown and lentiviral overexpression were applied to regulate VAMP2 expression. Bioinformatic analysis via GeneCards and STRING was performed to predict the interaction between VAMP2 and the PPAR pathway. Cell phenotypes and molecular alterations were detected by RT-qPCR, Western blotting, flow cytometry, ELISA and immunofluorescence. The PPAR inhibitor GW9662 was used to verify the regulatory relationship between VAMP2 and PPAR signaling.
Results: VAMP2 expression was significantly downregulated in Mg2+-free solution -treated neurons. VAMP2 overexpression increased cell viability, inhibited apoptosis and restored mitochondrial membrane potential (p<0.001). VAMP2 upregulated mitophagy-related proteins (LC3-II/I, PINK1, and Parkin), reduced ROS and pro-inflammatory cytokines (IL-1β, TNF-α), and balanced the expression of synaptic proteins NMDAR1 and GABAA1. Bioinformatic and experimental results demonstrated that VAMP2 acts as an upstream regulator to promote the expression and nuclear translocation of PPARα/γ. Blocking PPAR signaling with GW9662 completely abolished the protective effects of VAMP2, leading to impaired mitophagy, mitochondrial dysfunction and synaptic imbalance.
Conclusion: A novel VAMP2-PPAR-mitophagy axis was identified in seizure-injured neurons, which maintains mitochondrial integrity and alleviates neuronal damage. Targeting the crosstalk between vesicle trafficking and nuclear receptor signaling may provide potential therapeutic ideas for hyperexcitability-related neurodegenerative disorders.
Trial registration: Not applicable.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12868-026-01022-5.
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BibTeX
@article{li2026vamp2mediated,
title = {{VAMP2-mediated PPAR signaling modulates mitophagy and inflammatory responses in Mg2+-free induced HT22 neuronal cells}},
author = {Yan Li},
journal = {BMC Neuroscience},
year = {2026},
month = aug,
doi = {10.1186/s12868-026-01022-5},
url = {https://doi.org/10.1186/s12868-026-01022-5},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - VAMP2-mediated PPAR signaling modulates mitophagy and inflammatory responses in Mg2+-free induced HT22 neuronal cells
AU - Yan Li
PY - 2026
DA - 2026/08/10
JO - BMC Neuroscience
DO - 10.1186/s12868-026-01022-5
UR - https://doi.org/10.1186/s12868-026-01022-5
AB - Objective: To explore the neuroprotective effects and molecular mechanism of the VAMP2-mediated PPAR signaling pathway on neuronal mitophagy using an in vitro seizure-like injury model. Methods: A seizure model was established by culturing mouse hippocampal HT22 cells in Mg2+-free medium. siRNA-mediated gene knockdown and lentiviral overexpression were applied to regulate VAMP2 expression. Bioinformatic analysis via GeneCards and STRING was performed to predict the interaction between VAMP2 and the PPAR pathway. Cell phenotypes and molecular alterations were detected by RT-qPCR, Western blotting, flow cytometry, ELISA and immunofluorescence. The PPAR inhibitor GW9662 was used to verify the regulatory relationship between VAMP2 and PPAR signaling. Results: VAMP2 expression was significantly downregulated in Mg2+-free solution -treated neurons. VAMP2 overexpression increased cell viability, inhibited apoptosis and restored mitochondrial membrane potential (p<0.001). VAMP2 upregulated mitophagy-related proteins (LC3-II/I, PINK1, and Parkin), reduced ROS and pro-inflammatory cytokines (IL-1β, TNF-α), and balanced the expression of synaptic proteins NMDAR1 and GABAA1. Bioinformatic and experimental results demonstrated that VAMP2 acts as an upstream regulator to promote the expression and nuclear translocation of PPARα/γ. Blocking PPAR signaling with GW9662 completely abolished the protective effects of VAMP2, leading to impaired mitophagy, mitochondrial dysfunction and synaptic imbalance. Conclusion: A novel VAMP2-PPAR-mitophagy axis was identified in seizure-injured neurons, which maintains mitochondrial integrity and alleviates neuronal damage. Targeting the crosstalk between vesicle trafficking and nuclear receptor signaling may provide potential therapeutic ideas for hyperexcitability-related neurodegenerative disorders. Trial registration: Not applicable. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s12868-026-01022-5.
SN - 1471-2202
ER -