Guan Jiaxin, Wu Pengfei, Liu Meiling, Jiang Chuanlu, Meng Xiangqi, Wu Xiaowei, Lu Meijiao, Fan Ying, Gan Lu
Department of Geriatrics, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin, Heilongjiang 150081, China.
Department of Neurosurgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, China; Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu Medical University, Bengbu 233030, China.
Brain Behav Immun. 2025 Mar;125:21-32. doi: 10.1016/j.bbi.2024.12.022. Epub 2024 Dec 17.
Alzheimer's disease (AD), characterized by cognitive and behavioral abnormalities, is the most prevalent neurodegenerative disease worldwide. Neuroinflammation, which is induced by microglial activation, resulting in the expression of a multitude of inflammatory factors, is one of the principal characteristics of AD. Herein, we found that Egln3 is differentially expressed in microglia in the brains of AD mice. Egln3 is a member of the Egln family of proline hydroxylases, which regulates a variety of biological processes, including transcription, the cell cycle, and apoptosis, through hydroxylation, ubiquitylation, and participation in glycolysis. To further observe the effects of Egln3 on cognitive function, we utilized APP/PS1 mice as a pathological model of AD to conduct behavioral experiments and assess the expression levels of Aβ and inflammatory factors. The specific mechanisms by which Egln3 affects microglial activation were analyzed using in vitro experiments and transcriptome sequencing. The results of these analyses demonstrated that Egln3 is highly expressed in microglia in AD. Inhibition of Egln3 expression in the brains of APP/PS1 mice improves neuroinflammatory responses and cognitive function, indicating that a high expression of Egln3 promotes AD progression. Furthermore, our findings indicate that Egln3 could activate the MAPK pathway, which in turn contributes to the aggravation of neuroinflammation. Inhibition of the MAPK pathway results in attenuation of the pro-inflammatory state of microglia. Consequently, Egln3 may exacerbate neuroinflammation and promote AD progression via the MAPK pathway in microglia, making it a promising target for AD-related therapies.
阿尔茨海默病（AD）以认知和行为异常为特征，是全球最常见的神经退行性疾病。由小胶质细胞激活诱导的神经炎症导致多种炎症因子的表达，是AD的主要特征之一。在此，我们发现Egln3在AD小鼠大脑中的小胶质细胞中差异表达。Egln3是脯氨酸羟化酶Egln家族的成员，它通过羟基化、泛素化和参与糖酵解来调节包括转录、细胞周期和细胞凋亡在内的多种生物学过程。为了进一步观察Egln3对认知功能的影响，我们利用APP/PS1小鼠作为AD的病理模型进行行为实验，并评估Aβ和炎症因子的表达水平。使用体外实验和转录组测序分析了Egln3影响小胶质细胞激活的具体机制。这些分析结果表明，Egln3在AD的小胶质细胞中高表达。抑制APP/PS1小鼠大脑中Egln3的表达可改善神经炎症反应和认知功能，表明Egln3的高表达促进AD进展。此外，我们的研究结果表明，Egln3可激活MAPK通路，进而导致神经炎症加剧。抑制MAPK通路可导致小胶质细胞促炎状态的减弱。因此，Egln3可能通过小胶质细胞中的MAPK通路加剧神经炎症并促进AD进展，使其成为AD相关治疗的一个有前景的靶点。
