The Expression of Interleukin-1β is Regulated by DNA Methylation in Microglia to Mediate Postoperative Cognitive Dysfunction in Aged Mice

Abstract Postoperative cognitive dysfunction (POCD) is a common postoperative complication in elderly individuals. Neuroinflammation is closely related to its occurrence. However, the exact molecular mechanism underlying this link is undetermined. This study aimed to establish a mouse model of POCD to explore the role of DNA methylation in regulating the expression of interleukin-1β (IL-1β), which mediates the occurrence of POCD in aged mice. The POCD model was established by exploratory laparotomy and evaluated by novel object and Y-maze tests. We also assessed IL-1β production in the dorsal hippocampus and the expression of the DNA methylation-related proteins DNA methyltransferase 3a (DNMT3a), DNA methyltransferase 3b (DNMT3b), and methyl CpG binding protein 2 (MeCP2). Methylation specific PCR (MSP), methylated DNA immunoprecipitation (MeDIP) and DNA methylation sequencing in IL-1β promoter were used to explore the regulation of IL-1β by DNA methylation in this model. Finally, Golgi-Cox staining and Western blotting were used to further explore the role and potential mechanisms of IL-1β in POCD. Cognitive impairment was observed in aged but not adult mice. In aged mice, the microglia cells in the dorsal hippocampus were activated, while the DNA methylation in the IL-1β promoter was decreased. Interestingly, the global DNA methylation in the dorsal hippocampus was unchanged. IL-1β inhibition prevented surgery-induced cognitive decline and dysfunction of synaptic plasticity. Overall, these results indicated that DNA methylation regulation of IL-1β expression may be an important mechanism increasing the susceptibility to POCD.

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The Expression of Interleukin-1β Is Regulated by DNA Methylation in Microglia of Hippocampus to Participate Postoperative Cognitive Dysfunction in Aged Mice

10.21203/rs.3.rs-670804/v1 ◽

2021 ◽

Author(s):

Yin Gao ◽

Li Yang ◽

Xiu Yang ◽

Jing-Ru Hao ◽

Xiao-Ran Shen ◽

...

Keyword(s):

Dna Methylation ◽

Synaptic Plasticity ◽

Cognitive Dysfunction ◽

Western Blotting ◽

Dorsal Hippocampus ◽

The Elderly ◽

Aged Mice ◽

Promoter Dna Methylation ◽

Promoter Dna

Abstract BackgroundPostoperative cognitive dysfunction (POCD) is one of the common postoperative complications in the elderly. The main clinical manifestation is memory impairment, which can cause permanent damage and even dementia in severe cases. However, the pathogenesis of POCD is still unknown. Age and neuroinflammation are known to be closely related to its occurrence, while DNA methylation is very important for transcriptional silencing and neuroinflammation. Consequently, this study intended to establish a mouse model of POCD to explore the role of DNA methylation in regulating the expression of interleukin-1β which participated POCD in aged mice.MethodsPOCD model was established by exploratory laparotomy and evaluated by new object experiment and Y maze test. In addition, ELISA, RT-PCR, Western blotting, immunofluorescence, microglia isolation and flow cytometry methods were used to detect the inflammatory state of dorsal hippocampal after surgery. Moreover, MSP, MeDIP and IL-1β promoter DNA methylation sequencing were used to explore the regulation of DNA methylation on IL-1β in this model. Finally, Golgi staining and Western blotting were used to further explore the role of IL-1β in POCD and its possible mechanisms. ResultsCognitive impairment was observed in aged but not adult mice at 1 day after surgery. There was a significant correlation between the level of IL-1β in dorsal hippocampus and the performance of cognitive function. The microglia in the dorsal hippocampus was activated and the IL-1β promoter DNA methylation was decreased in the aged mice. The increased expression of IL-1β impaired synaptic plasticity and hippocampus-dependent memory formation. Intracerebroventricular administration of IL-1β receptor antagonist could prevent the cognitive impairment of aged mice after surgery, reverse the decrease of dendritic spine density and synapse-associated protein expression induced by surgery.ConclusionDNA methylation regulation may be an important mechanism for greater susceptibility to POCD in aged mice by regulating the expression of IL-1β. IL-1β inhibiting prevented surgery-induced cognitive decline and synaptic plasticity dysfunction. The research also provided a new target for the clinical prevention of the occurrence of POCD in the elderly.

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High-Pressure Pneumoperitoneum Aggravates Surgery-Induced Neuroinflammation and Cognitive Dysfunction in Aged Mice

Mediators of Inflammation ◽

10.1155/2020/6983193 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8

Author(s):

Bo Lu ◽

Hui Yuan ◽

Xiaojie Zhai ◽

Xiaoyu Li ◽

Jinling Qin ◽

...

Keyword(s):

High Pressure ◽

Cognitive Dysfunction ◽

Microglial Activation ◽

Postoperative Cognitive Dysfunction ◽

Abdominal Pressure ◽

Common Complication ◽

Operative Field ◽

Aged Patients ◽

Aged Mice ◽

Postoperative Cognitive Impairment

Postoperative cognitive dysfunction (POCD) is a common complication after surgery, especially in aged patients. Neuroinflammation has been closely associated with the development of POCD. While the contribution of pneumoperitoneum to the systemic inflammation has been well documented, the effect of pneumoperitoneal pressure on neuroinflammation and postoperative cognitive function remains unclear. In this study, we showed that high-pressure pneumoperitoneum promoted the postoperative neuroinflammation and microglial activation in the hippocampus and aggravated the postoperative cognitive impairment in aged mice. These results support the requirement to implement interventions with lower intra-abdominal pressure, which allows for adequate exposure of the operative field rather than a routine pressure.

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Multiple Anesthesia/Surgery Cannot Impair Reference Memory in Adult Mice

Mediators of Inflammation ◽

10.1155/2020/3736912 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8 ◽

Cited By ~ 1

Author(s):

Xiaoxin Zhou ◽

Jian Lu ◽

Tong Wu ◽

Xuliang Jiang ◽

Weitian Tian ◽

...

Keyword(s):

Central Nervous System ◽

Cognitive Function ◽

Cognitive Dysfunction ◽

Postoperative Cognitive Dysfunction ◽

Reference Memory ◽

Central Nervous System Inflammation ◽

Mortality And Morbidity ◽

Adult Mice ◽

Short Period ◽

Cholinergic Markers

Postoperative cognitive dysfunction increases mortality and morbidity in perioperative patients. Numerous studies have demonstrated that multiple surgery/anesthesia during the neurodevelopmental period affects cognitive function, whereas a single anesthesia/surgery rarely causes cognitive dysfunction in adults. However, whether adults who undergo multiple anesthesia/surgery over a short period will experience cognitive dysfunction remains unclear. In this study, central nervous system inflammation and changes in cholinergic markers were investigated in adult mice subjected to multiple laparotomy procedures over a short period of time. The results showed that despite the increased expression of IL-6 and TNF-α in the hippocampus after multiple operations and the activation of microglia, multiple anesthesia/surgery did not cause a decline in cognitive function in adult mice. There were no changes in the cholinergic markers after multiple anesthesia/surgery.

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