Hyperoxygenation Treatment Reduces Beta-amyloid Deposition via MeCP2-dependent Upregulation of MMP-2 and MMP-9 in the Hippocampus of Tg-APP/PS1 Mice.

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 decreases expression and to a lesser extent, and expression. In mice, siRNA-mediated knockdown in the hippocampus reduces expression, but not significantly and expression. The ChIP assay indicates that hyperoxygenation treatment in Tg-APP/PS1 mice increases MeCP2 binding to the promoter regions of , and 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.