CD33 Inhibition Of Downstream TREM2 Regulates Postoperative Cognitive Function In Aged Mice

Objective: Postoperative Cognitive Dysfunction(POCD)refers to short-term or long-term cognitive impairment that occurs after surgery.POCD is a complex syndrome that can include abnormalities in multiple aspects of cognitive function,such as attention,learning and memory,cognitive flexibility,spatial ability,language expression,and executive function.The mechanisms underlying POCD are not fully understood,but may be related to various factors,including surgical trauma,general anesthesia,synaptic damage,and inflammatory responses.CD33 is an immunoglobulin-type lectin that binds to sialic acid and can recognize and bind to sialylated pathogens,inhibit the TYROBP immune receptor tyrosine-based inhibition motif signal,and thus inhibit anti-inflammatory signal transduction in microglia.Increasing evidence supports the damaging role of CD33 in cognitive ability and brain function.TREM2(Triggering receptor expressed on myeloid cells 2)is a membrane glycoprotein mainly expressed on immune cells such as macrophages,dendritic cells,and microglia.In recent years,TREM2 has been a potential target for neurodegenerative disease treatment,and some studies have shown that activation or inhibition of TREM2 signaling can affect neuroinflammatory responses,brain injury repair processes,and provide new ideas and methods for the treatment of neurodegenerative diseases.Recent research has shown that TREM2 and CD33 play important roles in the pathogenesis of cognitive impairment-related diseases.For example,the levels of TREM2 in the cerebrospinal fluid of Alzheimer’s disease patients are significantly increased,while the expression levels of CD33 are relatively low.This may be because the upregulation of TREM2 can promote the clearance and repair of neurons,while CD33 may inhibit this process.In addition,the gene polymorphisms of TREM2 and CD33 are also related to the risk of Alzheimer’s disease.Overall,TREM2 and CD33 play complementary roles in immune cells and neurons,and the balance between them is crucial for maintaining normal immune and nervous system function.In-depth study of them can help to further reveal the pathogenesis of neurodegenerative diseases and provide new targets for the treatment and prevention of these diseases.Methods:1、The aged mice(9-12 months old)were randomly divided into 4 groups: control group,CD33 group,surgery group,and surgery+CD33 group.the CD33 group and surgery+CD33 group were injected with si RNA carrying the mouse CD33 gene into the mice by lateral ventricular injection.In this study,Morris water maze experiment was chosen to assess the behavioral performance of mice.The expression levels of IL-1β,IL-6,TNF-α,BDNF,and PSD-95 in the hippocampal region were detected by western blot on the 3rd and 7th postoperative days.The strips were scanned in grayscale followed by semi-quantitative analysis.2、BV2 cells were divided into five groups: control group,CD33 group,LPS group,CD33+LPS group and CD33+TREM2+LPS group.The control group BV2 cells were cultured routinely,the LPS group had 1ug/ml LPS added to the culture system,and the CD33 and TREM2 groups had targeting si RNA added to the culture system to establish a silencing model.When the operation was completed 48 hours later,q RT-PCR was used to detect the expression levels of related genes CD33 and TREM2 m RNA.Western blot was used to detect the expression levels of related genes CD33 and TREM2 and the expression levels of inflammatory factors IL-1β,IL6 and TNF-α.Results: Anesthesia and surgery resulted in spatial learning and memory impairment on the third day after surgery.Surgery resulted in down-regulation of TREM2 expression,increased expression of IL-1β,IL-6,and TNF-α,and decreased expression of PSD-95 and BDNF.The above changes can be reversed by exogenous injection of CD33 si RNA.Low expression of CD33 partially reversed postoperative cognitive impairment and enhanced the expression of PSD-95 and BDNF.In addition,reducing the expression of CD33 will improve the neuroinflammatory response induced by lipopolysaccharide,while reducing the expression of TREM2 and CD33 will reverse this effect and increase the expression of inflammatory factors IL-1β,IL-6 and TNF-α.Conclusion: CD33 may activate neuroinflammation by acting downstream of TREM2 and induce postoperative spatial learning memory deficits in aged C57/BL6 mice.The present study identified CD33 as a potential therapeutic target for POCD.