Journal Article

Cholecystokinin ameliorates cognitive impairment via inhibiting microglia phagocytosis of excitatory synapses in sepsis-associated encephalopathy mice

Piao, Guangxi, Li, Zhen, Li, Yitong, Liu, Taotao, Chen, Lei, Hong, Jingshu, Guo, Xiangyang, Chen, Luhua, Wang, Jie, Gao, Yubo, Li, Zhengqian, Wang, Qian, Liu, Kaixi, Du, Ailian

2025

Overview

Background Sepsis-associated encephalopathy (SAE) is characterised by cognitive impairment and is a common complication in patients with sepsis. Microglia are involved in various cognitive impairment-related diseases through phagocytic synapses. Cholecystokinin (CCK), an abundant neuropeptide in the brain, is closely related to cognitive function. However, the role of CCK in SAE and the relationship between CCK and microglial phagocytosis of synapses are unknown. Methods Lipopolysaccharide (LPS) was used to construct SAE models in 3-month-old male mice and BV2 microglial cells. To investigate the effects of CCK on cognitive impairment in SAE model mice, we used exogenous CCK injection into the dorsal hippocampal CA1 region or the chemogenetic activation of CCK-positive neurons to promote endogenous CCK release. Morris water maze and fear conditioning test were used to assess cognitive function in mice. RNA sequencing was performed to explore the potential signalling pathways involved in CCK-induced neuroprotection. Western blot and immunofluorescence were used to assess the effects of CCK on microglial phagocytosis of synapses, neurotoxic astrocytes, and excitatory synapses. Whole-cell recording was used to determine excitatory synaptic transmission. Results LPS successfully established in vivo and in vitro models of SAE. Both exogenous CCK injection and activation of CCK-positive neurons in hippocampal CA1 region attenuated cognitive impairment in SAE mice. Mechanistically, CCK significantly alleviated excitatory synaptic plasticity damage via inhibiting complement 1q (C1q)-mediated microglial phagocytosis of synapses and neurotoxic astrocyte polarisation. Moreover, in vitro SAE model of BV2 cells demonstrated that CCK exerts neuroprotective effects through microglial CCK2-type receptor. Conclusions CCK may alleviate cognitive impairment by inhibiting microglia C1q-mediated phagocytosis of excitatory synapses, suggesting that both CCK drugs and specific activation of CCK-positive neurons are potential treatments for SAE.

• Publisher: BioMed Central,BioMed Central Ltd,BMC
• Subject: Analysis / Animals / Biomedical and Life Sciences / Biomedicine / Care and treatment / Cholecystokinin / Cholecystokinin - pharmacology / Cholecystokinin - therapeutic use / Cognition disorders / Cognitive Dysfunction - drug therapy / Cognitive Dysfunction - etiology / Cognitive Dysfunction - metabolism / Cognitive Dysfunction - pathology / Complement 1q / Complications and side effects / Development and progression / Encephalopathy / Excitatory synapse / Health aspects / Immunology / Infection / Lipopolysaccharides - toxicity / Male / Mice / Mice, Inbred C57BL / Microglia / Microglia - drug effects / Microglia - metabolism / Neurobiology / Neurology / Neurons / Neurosciences / Phagocytosis / Phagocytosis - drug effects / Phagocytosis - physiology / Risk factors / RNA / RNA sequencing / Sepsis / Sepsis-associated encephalopathy / Sepsis-Associated Encephalopathy - chemically induced / Sepsis-Associated Encephalopathy - complications / Sepsis-Associated Encephalopathy - drug therapy / Sepsis-Associated Encephalopathy - metabolism / Sepsis-Associated Encephalopathy - pathology / Synapses - drug effects / Synapses - metabolism