PDF(Pubmed)
Abstract：
Analyzing changes in gene expression within specific brain regions of individuals with Type 2 Diabetes (T2DM) who do not exhibit significant cognitive deficits can yield valuable insights into the mechanisms underlying the progression towards a more severe phenotype. In this study, transcriptomic analysis of the cortex and hippocampus of mice with long-term T2DM revealed alterations in the expression of 28 genes in the cerebral cortex and 15 genes in the hippocampus. Among these genes, six displayed consistent changes in both the cortex and hippocampus: Interferon regulatory factor 7 (Irf7), Hypoxia-inducible factor 3 alpha (Hif-3α), period circadian clock 2 (Per2), xanthine dehydrogenase (Xdh), and Transforming growth factor β-stimulated clone 22/TSC22 (Tsc22d3) were upregulated, while Claudin-5 (Cldn5) was downregulated. Confirmation of these changes was achieved through RT-qPCR. At the protein level, CLDN5 and IRF7 exhibited similar alterations, with CLDN5 being downregulated and IRF7 being upregulated. In addition, the hippocampus and cortex of the T2DM mice showed decreased levels of IκBα, implying the involvement of NF-κB pathways as well. Taken together, these results suggest that the weakening of the blood-brain barrier and an abnormal inflammatory response via the Interferon 1 and NF-κB pathways underlie cognitive impairment in individuals with long-standing T2DM.
摘要：
分析不表现出显著认知缺陷的2型糖尿病(T2DM)个体的特定脑区域内的基因表达变化可以产生对朝向更严重表型进展的潜在机制的有价值的见解。在这项研究中,长期T2DM小鼠的皮质和海马的转录组学分析显示，大脑皮质中28个基因和海马中15个基因的表达发生了变化。在这些基因中,六个在皮质和海马中显示出一致的变化：干扰素调节因子7（Irf7），缺氧诱导因子3α（Hif-3α），周期昼夜节律时钟2（Per2），黄嘌呤脱氢酶（Xdh），和转化生长因子β刺激的克隆22/TSC22（Tsc22d3）上调，而Claudin-5（Cldn5）下调。通过RT-qPCR实现这些变化的确认。在蛋白质水平，CLDN5和IRF7表现出相似的改变，CLDN5下调，IRF7上调。此外,2型糖尿病小鼠海马和皮质组织IκBα水平降低,这也暗示了NF-κB通路的参与。一起来看,这些结果表明,血脑屏障的减弱和通过干扰素1和NF-κB通路的异常炎症反应是长期T2DM患者认知损害的基础.
