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A 3'UTR modification of the TNF-α mouse gene increases peripheral TNF-α and modulates the Alzheimer-like phenotype in 5XFAD mice.
Scientific Reports ( IF 3.8 ) Pub Date : 2020-05-26 , DOI: 10.1038/s41598-020-65378-2
Nikoleta Kalovyrna 1 , Olympia Apokotou 1 , Sotiria Boulekou 1 , Evi Paouri 1 , Athena Boutou 1 , Spiros Georgopoulos 1
Affiliation  

Tumor necrosis factor-α (TNF-α) is a pro-inflammatory cytokine, involved in Alzheimer’s disease pathogenesis. Anti-TNF-α therapeutic approaches currently used in autoimmune diseases have been proposed as a therapeutic strategy in AD. We have previously examined the role of TNF-α and anti-TNF-α drugs in AD, using 5XFAD mice, and we have found a significant role for peripheral TNF-α in brain inflammation. Here we investigated the role of mouse TNF-α on the AD-like phenotype of 5XFAD mice using a knock-in mouse with deletion of the 3’UTR of the endogenous TNF-α (TNFΔARE/+) that develops rheumatoid arthritis and Crohn’s disease. 5XFAD/TNFΔARE/+ mice showed significantly decreased amyloid deposition. Interestingly, microglia but not astrocytes were activated in 5XFAD/ TNFΔARE/+ brains. This microglial activation was associated with increased infiltrating peripheral leukocytes and perivascular macrophages and synaptic degeneration. APP levels and APP processing enzymes involved in Aβ production remained unchanged, suggesting that the reduced amyloid burden can be attributed to the increased microglial and perivascular macrophage activation caused by TNF-α. Peripheral TNF-α levels were increased while brain TNF-α remained the same. These data provide further evidence for peripheral TNF-α as a mediator of inflammation between the periphery and the brain.



中文翻译:

TNF-α 小鼠基因的 3'UTR 修饰可增加外周 TNF-α 并调节 5XFAD 小鼠的阿尔茨海默样表型。

肿瘤坏死因子-α (TNF-α) 是一种促炎细胞因子,参与阿尔茨海默病的发病机制。目前用于自身免疫性疾病的抗 TNF-α 治疗方法已被提议作为 AD 的治疗策略。我们之前使用 5XFAD 小鼠研究了 TNF-α 和抗 TNF-α 药物在 AD 中的作用,我们发现外周 TNF-α 在脑炎症中具有重要作用。在这里,我们使用敲入小鼠,研究了小鼠 TNF-α 对 5XFAD 小鼠 AD 样表型的作用,该小鼠删除了内源性 TNF-α (TNF ΔARE/+ ) 的 3'UTR,导致类风湿性关节炎和克罗恩病疾病。5XFAD/TNF ΔARE/+小鼠显示淀粉样蛋白沉积显着减少。有趣的是,在 5XFAD/TNF ΔARE/+大脑中,小胶质细胞而不是星形胶质细胞被激活。这种小胶质细胞的激活与浸润性外周白细胞和血管周围巨噬细胞的增加以及突触变性有关。参与 Aβ 生成的 APP 水平和 APP 加工酶保持不变,这表明淀粉样蛋白负荷的减少可归因于 TNF-α 引起的小胶质细胞和血管周围巨噬细胞活化的增加。外周 TNF-α 水平增加,而脑 TNF-α 水平保持不变。这些数据为外周 TNF-α 作为外周和大脑之间炎症介质提供了进一步的证据。

更新日期:2020-05-26
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