糖尿病小鼠早期症状阶段海马和大脑皮层中 Cldn5 的缺失和 Irf7 的增加。

IF 4.6 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM Nutrition & Diabetes Pub Date : 2024-08-15 DOI:10.1038/s41387-024-00325-y
Marta Carús-Cadavieco, Sandra González de la Fuente, Inés Berenguer López, Miguel A Serrano-Lope, Begoña Aguado, Francesc Guix, Ernest Palomer, Carlos G Dotti
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摘要

2型糖尿病(T2DM)患者如果没有表现出明显的认知障碍,对其特定脑区基因表达的变化进行分析,可以帮助我们深入了解其向更严重表型发展的机制。在这项研究中,对长期患有 T2DM 的小鼠大脑皮层和海马的转录组分析显示,大脑皮层有 28 个基因的表达发生了改变,海马有 15 个基因的表达发生了改变。在这些基因中,有六个基因在大脑皮层和海马中的表达发生了一致的变化:干扰素调节因子7(Irf7)、缺氧诱导因子3α(Hif-3α)、昼夜节律周期时钟2(Per2)、黄嘌呤脱氢酶(Xdh)和转化生长因子β刺激克隆22/TSC22(Tsc22d3)上调,而Claudin-5(Cldn5)下调。这些变化通过 RT-qPCR 得到了证实。在蛋白质水平上,CLDN5 和 IRF7 表现出类似的变化,CLDN5 下调,IRF7 上调。此外,T2DM 小鼠海马和皮层中的 IκBα 水平下降,这意味着 NF-κB 通路也参与其中。综上所述,这些结果表明,血脑屏障的减弱以及通过干扰素1和NF-κB途径产生的异常炎症反应是长期患有T2DM的个体出现认知障碍的原因。
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Loss of Cldn5 -and increase in Irf7-in the hippocampus and cerebral cortex of diabetic mice at the early symptomatic stage.

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.

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来源期刊
Nutrition & Diabetes
Nutrition & Diabetes ENDOCRINOLOGY & METABOLISM-NUTRITION & DIETETICS
CiteScore
9.20
自引率
0.00%
发文量
50
审稿时长
>12 weeks
期刊介绍: Nutrition & Diabetes is a peer-reviewed, online, open access journal bringing to the fore outstanding research in the areas of nutrition and chronic disease, including diabetes, from the molecular to the population level.
期刊最新文献
Late eating is associated with poor glucose tolerance, independent of body weight, fat mass, energy intake and diet composition in prediabetes or early onset type 2 diabetes. Association of ultra-processed food consumption with cardiovascular risk factors among patients with type-2 diabetes mellitus. Gestational diabetes exacerbates intrauterine microbial exposure induced intestinal microbiota change in offspring contributing to increased immune response. Soluble receptors for advanced glycation endproducts are predictors of insulin sensitivity and affected by weight loss. Impaired brain glucose metabolism in glucagon-like peptide-1 receptor knockout mice.
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