Endogenous reactive oxygen species cause astrocyte defects and neuronal dysfunctions in the hippocampus: a new model for aging brain.
The etiology of astrocyte dysfunction is not well understood even though neuronal defects have been extensively studied in a variety of neuronal degenerative diseases. Astrocyte defects could be triggered by the oxidative stress that occurs during physiological aging. Here, we provide evidence that intracellular or mitochondrial reactive oxygen species (ROS) at physiological levels can cause hippocampal (neuronal) dysfunctions. Specifically, we demonstrate that astrocyte defects occur in the hippocampal area of middle-aged Tet-mev-1 mice with the SDHCV69Emutation. These mice are characterized by chronic oxidative stress. Even though both young adult and middle-aged Tet-mev-1 mice overproduced MitoSOX Red-detectable mitochondrial ROS compared to age-matched wild-type C57BL/6J mice, only young adult Tet-mev-1 mice upregulated manganese and copper/zinc superoxide dismutase (Mn- and Cu/Zn-SODs) activities to eliminate the MitoSOX Red-detectable mitochondrial ROS. In contrast, middle-aged Tet-mev-1 mice accumulated both MitoSOX Red-detectable mitochondrial ROS and CM-H2DCFDA-detectable intracellular ROS. These ROS levels appeared to be in the physiological range as shown by normal thiol and glutathione disulfide/glutathione concentrations in both young adult and middle-aged Tet-mev-1 mice relative to age-matched wild-type C57BL/6J mice. Furthermore, only middle-aged Tet-mev-1 mice showed JNK/SAPK activation and Ca2+overload, particularly in astrocytes. This led to decreasing levels of glial fibrillary acidic protein and S100β in the hippocampal area. Significantly, there were no pathological features such as apoptosis, amyloidosis, and lactic acidosis in neurons and astrocytes. Our findings suggest that the age-dependent physiologically relevant chronic oxidative stress caused astrocyte defects in mice with impaired mitochondrial electron transport chain functionality.
Department of Molecular Life Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.|Institute of Medical Sciences, Tokai University, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.
Takamasa
T
Ishii
Department of Molecular Life Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.
Yumi
Y
Takanashi
Department of Molecular Life Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.|School of Bioscience and Biotechnology, Tokyo University of Technology, 1404-1 Katakuramachi, Hachioji, Tokyo, 192-0982, Japan.
Koichi
K
Sugita
Department of Molecular Life Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.
Masaki
M
Miyazawa
Department of Molecular Life Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.
Rintaro
R
Yanagihara
Department of Molecular Life Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.|Support Center for Medical Research and Education, Tokai University, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.
Kayo
K
Yasuda
Department of Ophthalmology, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.
Hiromi
H
Onouchi
Support Center for Medical Research and Education, Tokai University, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.
Noboru
N
Kawabe
Department of Applied Biochemistry, Tokai University School of Engineering, 4-1-1 Kitakaname, Hiratsuka, Kanagawa, 259-1292, Japan.
Munehiro
M
Nakata
School of Bioscience and Biotechnology, Tokyo University of Technology, 1404-1 Katakuramachi, Hachioji, Tokyo, 192-0982, Japan.
Yorihiro
Y
Yamamoto
Department of Biology, Texas Christian University, Fort Worth, TX, 76129, USA.
Phil S
PS
Hartman
Department of Molecular Life Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa, 259-1193, Japan.
Naoaki
N
Ishii
D000375:Aging / Q000473:pathology*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology*; D015415:Biomarkers / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics; D008568:Memory; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D010084:Oxidation-Reduction; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism*; D009418:S100 Proteins / Q000378:metabolism; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000378:metabolism
D015415:Biomarkers; D017362:Cyclic AMP Response Element-Binding Protein; D005904:Glial Fibrillary Acidic Protein; D008565:Membrane Proteins; D017382:Reactive Oxygen Species; D009418:S100 Proteins; C582347:SDHC protein, mouse; D013482:Superoxide Dismutase; D048031:JNK Mitogen-Activated Protein Kinases; D002118:Calcium
Ca2+; JNK/SAPK; aging; astrocyte; mitochondria; oxidative stress