Endoplasmic Reticulum Autophagy Enhancement Alleviates Synaptic Plasticity Dysfunction and Ameliorates Cognitive Impairment in
SAE
Mice by Relieving
STING
Xiaofeng Guo, Daqing Yin, Zhonghua Zhang, Yuanyuan Zhao, Yali Zhang, Ying Jiang, Zhanying Zhao, Tongwen Sun, Feihu Zhou, Xijing Zhang 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 ( PKM2 fl/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.