Recently we reported that hyperoxygenation treatment reduces amyloid-beta accumulation and rescues cognitive impairment in the Tg-APP/PS1 mouse model of Alzheimer's disease. In the present study, we continue to investigate the mechanism by which hyperoxygenation reduces amyloid-beta deposition in the brain. Hyperoxygenation treatment induces upregulation of matrix metalloproteinase-2 (MMP-2), MMP-9, and tissue plasminogen activator (tPA), the endopeptidases that can degrade amyloid-beta, in the hippocampus of Tg-APP/PS1 mice. The promoter regions of the three proteinase genes all contain potential binding sites for MeCP2 and Pea3, which are upregulated in the hippocampus after hyperoxygenation. Hyperoxygenation treatment in HT22 neuronal cells increases MeCP2 but not Pea3 expression. In HT22 cells, siRNA-mediated knockdown of Mecp2 decreases Mmp-9 expression and to a lesser extent, Mmp-2 and tPA expression. In mice, siRNA-mediated Mecp2 knockdown in the hippocampus reduces Mmp-9 expression, but not significantly Mmp-2 and tPA expression. The ChIP assay indicates that hyperoxygenation treatment in Tg-APP/PS1 mice increases MeCP2 binding to the promoter regions of Mmp-2 , Mmp-9 and tPA genes in the hippocampus. Together, these results suggest that hyperoxygenation increases the expression of MMP-2, MMP-9, and tPA, of which MMP-9 is upregulated via MeCP2 in neuronal cells, and MMP-2 and tPA are upregulated through MeCP2 and other nuclear factors.

中文翻译：

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高氧治疗通过 Tg-APP/PS1 小鼠海马体中 MMP-2 和 MMP-9 的 MeCP2 依赖性上调减少 β-淀粉样蛋白沉积。

最近我们报道，在阿尔茨海默病的 Tg-APP/PS1 小鼠模型中，过度氧合治疗减少了淀粉样蛋白-β 的积累并挽救了认知障碍。在本研究中，我们继续研究高氧合减少大脑中淀粉样蛋白-β 沉积的机制。高氧治疗诱导 Tg-APP/PS1 小鼠海马中基质金属蛋白酶-2 (MMP-2)、MMP-9 和组织纤溶酶原激活剂 (tPA) 的上调，这些内肽酶可以降解淀粉样蛋白-β。三个蛋白酶基因的启动子区域都包含 MeCP2 和 Pea3 的潜在结合位点，它们在高氧合后在海马中上调。HT22 神经元细胞中的高氧处理会增加 MeCP2 的表达，但不会增加 Pea3 的表达。在 HT22 细胞中，siRNA 介导的Mecp2降低Mmp-9表达，并在较小程度上降低Mmp-2和tPA表达。在小鼠中，siRNA 介导的海马Mecp2敲低降低了Mmp-9 的表达，但不会显着降低Mmp-2和tPA 的表达。ChIP 分析表明，Tg-APP/PS1 小鼠的过度氧合处理增加了 MeCP2 与Mmp-2、Mmp-9和tPA启动子区域的结合海马体中的基因。总之，这些结果表明，高氧合增加了 MMP-2、MMP-9 和 tPA 的表达，其中 MMP-9 在神经元细胞中通过 MeCP2 上调，而 MMP-2 和 tPA 通过 MeCP2 和其他核因子上调。