RESUMO
At present, many drugs were developed based on the main pathological feature of Alzheimer′s disease (AD): "β-amyloid cascade hypothesis and abnormal tau protein aggregation" as targets, but the efficacy is unsatisfactory. With the progress on the study of pathological mechanism of AD, the role of microglia and their related expression genes, such as TREM2, CD 33, ABCA7 gene and their related signal transduction pathways in the pathological mechanism of AD has been paid more and more attention. The study on AD biomarkers and therapeutic targets based on microglia and their related expression genes has also increased significantly. This review will mainly focus on the pathophysiology of microglia, the mechanism of microglia in AD, the biomarkers related to microglia and the drug treatment of AD.
RESUMO
Objective:To explore the effects and possible mechanisms of Tyrobp gene on neuroinflammation in Tourette's syndrome mice.Methods:Twenty C57BL/ 6J and Tyrobp knock-out male mice aged 6 weeks were randomly divided into 4 groups according to random number table method: WT+ NS group, Tyrobp -/-+ NS group, WT+ IDPN group and Tyrobp -/-+ IDPN group. Mice in WT+ IDPN group and Tyrobp -/-+ IDPN group were injected with IDPN intraperitoneally at a dose of 150 mg/kg·d, while mice in WT+ NS group and Tyrobp -/-+ NS group were injected with equal volume of normal saline, once a day for 7 days. Then stereotypical behavior of mice were evaluated. Western blot was used to detect the levels of Tyrobp, TNF-α, IL-6, IL-1β, TLR4, Myd88, p-NF-κB p65 and p-IκBα in the striatum of mice. Immunofluorescence staining was used to observe the activation of microglia. Statistical analysis was performed using GraphPad Prism 8.0 software, and t-test was used for comparison between two groups. One-way ANOVA was used to compare the means of multiple samples, and LSD test was used for further pairwise comparison. Results:The results of behavior assessment showed that there were significant differences in the motor stereotypic behavior and categorical stereotypic behavior score( F=270.9, 379.7, P<0.01), and the scores in WT+ IDPN group were higher than those in Tyrobp -/-+ IDPN group (motor stereotypic behavior: (3.23±0.26), (2.13±0.21), t=9.02, P<0.05; categorical stereotypic behavior: (45.80±4.29), (26.60±3.48), t=12.00, P<0.05). Western blot results showed that there were significant differences in the protein expression level of TNF-α, IL-6, IL-1β, TLR4, Myd88, p-NF-κB p65 and p-IκBα ( F=29.07, 23.09, 39.36, 57.6, 52.55, 15.50, 40.48, all P<0.05), the level of those in WT + IDPN group was higher than those in WT+ NS group( t=8.31, 7.37, 8.13, 11.43, 10.47, 6.05, 9.96, all P<0.05), Tyrobp -/-+ IDPN group was higher than Tyrobp -/-+ NS group ( t=3.60, 3.00, 5.84, 4.81, 3.59, 2.26, 4.68, all P<0.05), and WT + IDPN group was higher than Tyrobp -/-+ IDPN group ( t=3.97, 3.93, 4.14, 6.40, 7.63, 3.45, 3.03, all P<0.05). Immunofluorescence showed that microglial cells in the striatum region of mice in WT+ IDPN group and Tyrobp -/-+ IDPN group were enlarged and microglial cells were activated, and the activation pattern of microglial cells in WT+ IDPN group was more obvious than that in Tyrobp -/-+ IDPN group. Conclusion:Tyrobp may be involved in the pathogenesis of Tourette's syndrome by promoting neuroinflammation mediated by TLR4/Myd88/NF-κB signaling pathway.