TY - JOUR
T1 - Hyperoxygenation treatment reduces beta-amyloid deposition via mecp2-dependent upregulation of MMP-2 and MMP-9 in the hippocampus of Tg-APP/PS1 mice
AU - Choi, Juli
AU - Kwon, Hyejin
AU - Han, Pyung Lim
N1 - Funding Information:
This research was supported by a grant (2021R1A2B5B02002245) from the Ministry of Science, ICT and Future Planning, Republic of Korea.
Publisher Copyright:
© Experimental Neurobiology 2021.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - Beta-amyloid
KW - Hyperoxygenation
KW - MMP-2
KW - MMP-9
KW - MeCP2
UR - http://www.scopus.com/inward/record.url?scp=85115955343&partnerID=8YFLogxK
U2 - 10.5607/EN21014
DO - 10.5607/EN21014
M3 - Article
AN - SCOPUS:85115955343
SN - 1226-2560
VL - 30
SP - 294
EP - 307
JO - Experimental Neurobiology
JF - Experimental Neurobiology
IS - 4
ER -