Department of Clinical Laboratory Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China.
J Neuroinflammation. 2022 Jul 12;19(1):180. doi: 10.1186/s12974-022-02548-1.
Studies have suggested that many down-regulated miRNAs identified in the brain tissue or serum of Alzheimer's disease (AD) patients were involved in the formation of senile plaques and neurofibrillary tangles. Specifically, our previous study revealed that microRNA-22-3p (miR-22-3p) was significantly down-regulated in AD patients. However, the molecular mechanism underlying the down-regulation of miR-22-3p has not been comprehensively investigated.
The ameliorating effect of miR-22-3p on apoptosis of the Aβ-treated HT22 cells was detected by TUNEL staining, flow cytometry, and western blotting. The cognition of mice with stereotaxic injection of agomir or antagomir of miR-22-3p was assessed by Morris water maze test. Pathological changes in the mouse hippocampus were analyzed using hematoxylin and eosin (HE) staining, Nissl staining, and immunohistochemistry. Proteomics analysis was performed to identify the targets of miR-22-3p, which were further validated using dual-luciferase reporter analysis and western blotting analysis.
The miR-22-3p played an important role in ameliorating apoptosis in the Aβ-treated HT22 cells. Increased levels of miR-22-3p in the mouse hippocampus improved the cognition in mice. Although the miR-22-3p did not cause the decrease of neuronal loss in the hippocampus, it reduced the Aβ deposition. Proteomics analysis revealed Sox9 protein as the target of miR-22-3p, which was verified by the luciferase reporter experiments.
Our study showed that miR-22-3p could improve apoptosis and reduce Aβ deposition by acting on Sox9 through the NF-κB signaling pathway to improve the cognition in AD mice. We concluded that miR-22-3p ameliorated AD by targeting Sox9 through the NF-κB signaling pathway in the hippocampus.
研究表明，在阿尔茨海默病（AD）患者的脑组织或血清中发现的许多下调的 miRNA 参与了老年斑和神经原纤维缠结的形成。具体来说，我们之前的研究表明 microRNA-22-3p（miR-22-3p）在 AD 患者中显著下调。然而，miR-22-3p 下调的分子机制尚未得到全面研究。
通过 TUNEL 染色、流式细胞术和 Western blot 检测 miR-22-3p 对 Aβ 处理的 HT22 细胞凋亡的改善作用。通过 Morris 水迷宫试验评估立体定向注射 miR-22-3p 激动剂或拮抗剂的小鼠的认知。通过苏木精和伊红（HE）染色、尼氏染色和免疫组织化学分析小鼠海马的病理变化。使用双荧光素酶报告分析和 Western blot 分析进一步验证蛋白质组学分析鉴定的 miR-22-3p 靶标。
miR-22-3p 在改善 Aβ 处理的 HT22 细胞凋亡中起重要作用。小鼠海马中 miR-22-3p 水平升高可改善小鼠认知。虽然 miR-22-3p 不会导致海马神经元丢失减少，但它可减少 Aβ 沉积。蛋白质组学分析显示 Sox9 蛋白是 miR-22-3p 的靶标，这通过荧光素酶报告实验得到验证。
我们的研究表明，miR-22-3p 可以通过 NF-κB 信号通路作用于 Sox9 来改善 AD 小鼠的凋亡和减少 Aβ 沉积，从而改善认知。我们得出结论，miR-22-3p 通过 NF-κB 信号通路在海马中靶向 Sox9 改善 AD。
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