Department of General medicine, Affiliated Hospital of Chengde Medical College, Chengde 067000, China.
Department of Dermatology, Affiliated Hospital of Chengde Medical College, Chengde 067000, China.
Neurologia (Engl Ed). 2023 Sep;38(7):486-494. doi: 10.1016/j.nrleng.2020.12.006.
Mir-146a-5p has been widely recognized as a critical regulatory element in the immune response. However, recent studies have shown that miR-146a-5p may also be involved in the development of Alzheimer disease (AD). Regrettably, the related mechanisms are poorly understood. Here, we investigated the effects of miR-146a in mice models and SH-SY5Y cells treated with amyloid β (Aβ).
To create a model of AD, SH-SY5Y cells were treated with Aβ and mice received intracerebroventricular injections of Aβ. Then, the transcriptional levels of miR-146a were estimated by real-time PCR. We transiently transfected the miR-146a-5p mimic/inhibitor into cells and mice to study the role of miR-146a. The role of signaling pathways including p38 and reactive oxygen species (ROS) was studied by using specific inhibitors. Aβ and amyloid-beta precursor protein (APP)levels were measured by immunoblotting. Furthermore, Aβ expression was analyzed by immunofluorescence and histochemical examinations.
Aβ-stimulated SH-SY5Y cells displayed increased transcriptional levels of miR-146a and APP. Moreover, the p38 MAPK signaling pathway and ROS production were activated upon stimulation with a miR-146a-5p mimic. However, treatment with a miR-146a-5p inhibitor decreased the levels of APP, ROS, and p-p38 MAPK. A similar phenomenon was also observed in the animals treated with Aβ, in which miR-146a upregulation increased the expression of Aβ, p-p38, and ROS, while the inhibition of miR-146a had the opposite effect. This suggests that miR-146a increases Aβ deposition and ROS accumulation via the p-p38 signaling pathway.
Our research demonstrates that miR-146a-5pa increases Aβ deposition by triggering oxidative stress through activation of MAPK signaling.
miR-146a-5p 已被广泛认为是免疫反应中关键的调节因子。然而，最近的研究表明，miR-146a-5p 也可能参与阿尔茨海默病（AD）的发生。遗憾的是，相关机制尚不清楚。在这里，我们研究了 miR-146a 在经淀粉样β（Aβ）处理的小鼠模型和 SH-SY5Y 细胞中的作用。
为了建立 AD 模型，用 Aβ 处理 SH-SY5Y 细胞，并用 Aβ 对小鼠进行侧脑室注射。然后，通过实时 PCR 估计 miR-146a 的转录水平。我们将 miR-146a-5p 模拟物/抑制剂瞬时转染到细胞和小鼠中，以研究 miR-146a 的作用。通过使用特定的抑制剂研究包括 p38 和活性氧（ROS）在内的信号通路的作用。通过免疫印迹测量 Aβ 和淀粉样前体蛋白（APP）的水平。此外，通过免疫荧光和组织化学检查分析 Aβ 的表达。
Aβ 刺激的 SH-SY5Y 细胞显示 miR-146a 和 APP 的转录水平增加。此外，刺激 miR-146a-5p 模拟物后，p38 MAPK 信号通路和 ROS 产生被激活。然而，用 miR-146a-5p 抑制剂处理会降低 APP、ROS 和 p-p38 MAPK 的水平。在接受 Aβ 治疗的动物中也观察到类似的现象，其中 miR-146a 的上调增加了 Aβ、p-p38 和 ROS 的表达，而 miR-146a 的抑制则产生相反的效果。这表明 miR-146a 通过激活 MAPK 信号增加 Aβ 沉积并引起 ROS 积累。
我们的研究表明，miR-146a-5pa 通过触发 MAPK 信号引起氧化应激增加 Aβ 沉积。
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