Endoplasmic Reticulum Autophagy Enhancement Alleviates Synaptic Plasticity Dysfunction and Ameliorates Cognitive Impairment in SAE Mice by Relieving STING‐Associated Inhibition of PKM2 Activity
4 affiliations
- 1Department of Critical Care Medicine, The First Medical Center of Chinese PLA General Hospital, Beijing, China.
- 2Department of Critical Care Medicine, The 988th Hospital of the PLA Joint Logistics Support Force, Zhengzhou, Henan, China.
- 3Department of Critical Care Medicine, Xijing Hospital, Air Force Medical University, Xi'an, Shaanxi, China.
- 4Department of Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Abstract
Background
The pathogenesis of cognitive impairment in patients with sepsis-associated encephalopathy (SAE) remains unclear. This study investigated whether enhancing micro-endoplasmic reticulum autophagy (micro-ER-phagy) could alleviate synaptic dysfunction and improve cognitive impairment in SAE mice models by relieving stimulator of interferon gene (STING)-associated inhibition of pyruvate kinase M2 (PKM2) activity.Methods
Male wild-type and neuron-specific PKM2 conditional knockout mice (PKM2fl/fl; hSyn-Cre⁺) were used. Cognitive function in SAE mice models was assessed using the Y-maze and contextual fear conditioning tests. Neuronal plasticity was examined using transmission electron microscopy and Golgi staining, whereas immunofluorescence staining and Western blotting were employed to determine the temporal and spatial expression patterns of related proteins.Results
Septic mice developed cognitive impairment. Hippocampal tissues of SAE mice exhibited synaptic plasticity dysfunction and glycolysis enhancement. Meanwhile, the hippocampus showed increased PKM2 expression and an altered ratio of PKM2 tetramers and dimers. In addition, phosphorylated STING significantly increased in concentration in hippocampal neurones and its knockdown improved cognitive function. However, this cognitive rescue failed in PKM2 conditional knockout mice treated with SAE. Finally, Sec62-mediated micro-ER-phagy promoted lysosomal degradation of STING, which relieved STING-mediated inhibition of PKM2 and improved synaptic plasticity and cognitive dysfunction in SAE mice.Conclusions
Elevated micro-ER-phagy may relieve the STING-associated inhibition of PKM2 activity, improve neuronal glycolysis and synaptic plasticity, and alleviate cognitive dysfunction in SAE mice.
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BibTeX
@article{guo2026endoplasmic,
title = {{Endoplasmic Reticulum Autophagy Enhancement Alleviates Synaptic Plasticity Dysfunction and Ameliorates Cognitive Impairment in SAE Mice by Relieving STING‐Associated Inhibition of PKM2 Activity}},
author = {Xiaofeng Guo and Daqing Yin and Zhonghua Zhang and Yuanyuan Zhao and Yali Zhang and Ying Jiang and Zhanying Zhao and Tongwen Sun and Feihu Zhou and Xijing Zhang},
journal = {CNS neuroscience \& therapeutics},
year = {2026},
month = oct,
doi = {10.1002/cns.71233},
url = {https://europepmc.org/article/PMC/PMC13717600},
note = {CC BY},
}
RIS
TY - JOUR
TI - Endoplasmic Reticulum Autophagy Enhancement Alleviates Synaptic Plasticity Dysfunction and Ameliorates Cognitive Impairment in SAE Mice by Relieving STING‐Associated Inhibition of PKM2 Activity
AU - Xiaofeng Guo
AU - Daqing Yin
AU - Zhonghua Zhang
AU - Yuanyuan Zhao
AU - Yali Zhang
AU - Ying Jiang
AU - Zhanying Zhao
AU - Tongwen Sun
AU - Feihu Zhou
AU - Xijing Zhang
PY - 2026
DA - 2026/10/29
JO - CNS neuroscience & therapeutics
DO - 10.1002/cns.71233
UR - https://europepmc.org/article/PMC/PMC13717600
AB - Background The pathogenesis of cognitive impairment in patients with sepsis-associated encephalopathy (SAE) remains unclear. This study investigated whether enhancing micro-endoplasmic reticulum autophagy (micro-ER-phagy) could alleviate synaptic dysfunction and improve cognitive impairment in SAE mice models by relieving stimulator of interferon gene (STING)-associated inhibition of pyruvate kinase M2 (PKM2) activity.Methods Male wild-type and neuron-specific PKM2 conditional knockout mice (PKM2fl/fl; hSyn-Cre⁺) were used. Cognitive function in SAE mice models was assessed using the Y-maze and contextual fear conditioning tests. Neuronal plasticity was examined using transmission electron microscopy and Golgi staining, whereas immunofluorescence staining and Western blotting were employed to determine the temporal and spatial expression patterns of related proteins.Results Septic mice developed cognitive impairment. Hippocampal tissues of SAE mice exhibited synaptic plasticity dysfunction and glycolysis enhancement. Meanwhile, the hippocampus showed increased PKM2 expression and an altered ratio of PKM2 tetramers and dimers. In addition, phosphorylated STING significantly increased in concentration in hippocampal neurones and its knockdown improved cognitive function. However, this cognitive rescue failed in PKM2 conditional knockout mice treated with SAE. Finally, Sec62-mediated micro-ER-phagy promoted lysosomal degradation of STING, which relieved STING-mediated inhibition of PKM2 and improved synaptic plasticity and cognitive dysfunction in SAE mice.Conclusions Elevated micro-ER-phagy may relieve the STING-associated inhibition of PKM2 activity, improve neuronal glycolysis and synaptic plasticity, and alleviate cognitive dysfunction in SAE mice.
SN - 1755-5930
SN - 1755-5949
ER -