Children's Hospital Capital Institute of Pediatrics, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100020, China.
Graduate School of Peking Union Medical College, Beijing, 100730, China.
J Neuroinflammation. 2024 Aug 21;21(1):208. doi: 10.1186/s12974-024-03189-2.
Obstructive sleep apnoea (OSA) is a sleep-disordered breathing characterized by intermittent hypoxia (IH) that may cause cognitive dysfunction. However, the impact of IH on molecular processes involved in cognitive function remains unclear.
C57BL / 6 J mice were exposed to either normoxia (control) or IH for 6 weeks. DNA hydroxymethylation was quantified by hydroxymethylated DNA immunoprecipitation (hMeDIP) sequencing. ten-eleven translocation 1 (Tet1) was knocked down by lentivirus. Specifically, cognitive function was assessed by behavioral experiments, pathological features were assessed by HE staining, the hippocampal DNA hydroxymethylation was examined by DNA dot blot and immunohistochemical staining, while the Wnt signaling pathway and its downstream effects were studied using qRT-PCR, immunofluorescence staining, and Luminex liquid suspension chip analysis.
IH mice showed pathological changes and cognitive dysfunction in the hippocampus. Compared with the control group, IH mice exhibited global DNA hydroxylmethylation in the hippocampus, and the expression of three hydroxylmethylases increased significantly. The Wnt signaling pathway was activated, and the mRNA and 5hmC levels of Wnt3a, Ccnd2, and Prickle2 were significantly up-regulated. Further caused downstream neurogenesis abnormalities and neuroinflammatory activation, manifested as increased expression of IBA1 (a marker of microglia), GFAP (a marker of astrocytes), and DCX (a marker of immature neurons), as well as a range of inflammatory cytokines (e.g. TNFa, IL3, IL9, and IL17A). After Tet1 knocked down, the above indicators return to normal.
Activation of Wnt signaling pathway by hippocampal Tet1 is associated with cognitive dysfunction induced by IH.
阻塞性睡眠呼吸暂停（OSA）是一种以间歇性低氧（IH）为特征的睡眠呼吸障碍，可能导致认知功能障碍。然而，IH 对涉及认知功能的分子过程的影响尚不清楚。
C57BL/6J 小鼠分别暴露于常氧（对照）或 IH 中 6 周。通过羟甲基化 DNA 免疫沉淀（hMeDIP）测序定量 DNA 羟甲基化。Tet1 通过慢病毒敲低。具体而言，通过行为实验评估认知功能，通过 HE 染色评估病理特征，通过 DNA 点印迹和免疫组化染色检测海马体 DNA 羟甲基化，同时通过 qRT-PCR、免疫荧光染色和 Luminex 液相悬浮芯片分析研究 Wnt 信号通路及其下游效应。
IH 小鼠的海马体出现病理变化和认知功能障碍。与对照组相比，IH 小鼠的海马体表现出全基因组 DNA 羟甲基化，三种羟甲基化酶的表达显著增加。Wnt 信号通路被激活，Wnt3a、Ccnd2 和 Prickle2 的 mRNA 和 5hmC 水平显著上调。进一步导致下游神经发生异常和神经炎症激活，表现为 IBA1（小胶质细胞标志物）、GFAP（星形胶质细胞标志物）和 DCX（未成熟神经元标志物）的表达增加，以及一系列炎症细胞因子（如 TNFa、IL3、IL9 和 IL17A）的表达增加。敲低 Tet1 后，上述指标恢复正常。
海马体 Tet1 激活 Wnt 信号通路与 IH 引起的认知功能障碍有关。
