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Objective To explore the hub genes and the potential targets in the treatment of diabetes with TREM2 mutation-related cognitive dysfunction with bioinformatics analysis. Methods The cases of differential genes (DEGs) of diabetes mellitus and TREM2 mutation-related cognitive dysfunction were obtained respectively by microarray data analysis, the common differential genes were obtained by intersection between the two diseases. GO analysis, KEGG and Reactome pathway analysis were performed on the selected differential genes. The protein-protein interaction(PPI) network was constructed using online database. Finally, the effects of diabetes and TREM2 on spatial learning and memory of mice were detected by water maze, and the expression of hub gene SNAP25 was detected by Western blot. Results In both datasets, 19 genes showed similar changes, mainly enriched in biological processes and pathways related to neurons and metabolism. According to PPI analysis, DNER, GFAP, GRM5 and SNAP25 were identified as hub genes. Trem2 gene knockout aggravated spatial learning and memory impairment in diabetic mice. The expression of SNAP25 in hippocampus of diabetes mice was significantly increased, and then decreased after Trem2 knockout. Conclusions This study identified 19 TREM2-related genes in diabetes with cognitive dysfunction, among which 4 hub genes were found. These results provide a new experimental basis for the treatment of diabetes patients with cognitive impairment.

Objective To explore the expression of triggering receptor expressed on myeloid cells 2 (TREM2) in high-glucose microglia and to investigate the role of TREM2 in the proliferation, migration and phagocytosis of high-glucose microglia. Methods Microglia cells were divided into control group and high-glucose treatment group(67.5 mmol/L glucose, 24 h). The microglia cells were counted and the expression of Iba1 and TREM2 was detected. TREM2 siRNA was transfected to detect the proliferation and migration of microglia. The amyloid β-peptide (Aβ) with a fluorescent tag was added to observe the phagocytosis of Aβ by microglia. Results Compared to normal microglia, the number of microglia significantly decreased after high-glucose treatment (P＜0.001), while the expression of TREM2 and Iba1 markedly increased (P＜0.001). High glucose and TREM2 did not affect the proliferation of microglia. Compared to the normal group, the migration of microglia significantly decreased after high-glucose treatment (P＜0.05) and TREM2 did not affect the migration ability of high-glucose microglia. Compared to the normal group, the phagocytosis of Aβ by microglia significantly decreased in the high-glucose treated group(P＜0.001). Furthermore, TREM2 knockdown further decreased the phagocytosis of Aβ by high-glucose microglia (P＜0.001). Conclusions The expression of TREM2 in microglia significantly increases after high-glucose treatment, which significantly affects phagocytosis of Aβ by microglia.

Background: Perioperative cerebral ischemia/reperfusion injury is a major contributor to postoperative death and cognitive dysfunction in patients. It was reported that morphine preconditioning (MP) can mimic ischemia/hypoxia preconditioning to protect against ischemia/reperfusion injury. However, the mechanism of MP on the ischemia/reperfusion-induced neuronal apoptosis has not been fully clarified., Methods: The middle cerebral artery occlusion/reperfusion (MCAO/R) model of mice and the oxygen-glucose deprivation/reoxygenation (OGD/R) model in primary cortical neurons were used to mimic ischemic stroke. In vivo, the infarct size was measured by using TTC staining; NDSS, Longa score system, and beam balance test were performed to evaluate the neurological deficits of mice; the expression of the protein was detected by using a western blot. In vitro, the viability of neurons was determined by using CCK-8 assay; the expression of protein and mRNA were assessed by using western blot, RT-qPCR, and immunofluorescent staining; the level of apoptosis was detected by using TUNEL staining., Results: MP can improve the neurological functions of mice following MCAO/R (P<0.001, n=10 per group). MP can decrease the infarct size (P<0.001, n=10 per group) and the level of cleaved-caspase-3 of mice following MCAO/R (P<0.01 or 0.001, n=6 per group). MP can increase the levels of cPKCγ membrane translocation, p-p65, and cFLIPL, and decrease the levels of cleaved-caspase-8, 3 in neurons after OGD/R or MCAO/R 1 d (P<0.05, 0.01 or 0.001, n=6 per group). In addition, MP could alleviate OGD/R-induced cell apoptosis (P<0.001, n=6 per group)., Conclusion: MP alleviates ischemia/reperfusion-induced Caspase 8-dependent neuronal apoptosis through the cPKCγ-NF-κB-cFLIPL pathway., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)