Endogenous reactive oxygen species cause astrocyte defects and neuronal dysfunctions in the hippocampus: a new model for aging brain. Issue 1 (13th September 2016)

• Record Type: Journal Article
• Authors: Ishii, Takamasa; Takanashi, Yumi; Sugita, Koichi; Miyazawa, Masaki; Yanagihara, Rintaro; Yasuda, Kayo; Onouchi, Hiromi; Kawabe, Noboru; Nakata, Munehiro; Yamamoto, Yorihiro; Hartman, Phil S.; Ishii, Naoaki
• Is Part Of: Aging cell. Volume 16:Issue 1(2017)
• Page Start: 39
• Page End: 51
• Publication Date: 2016-09-13
• Subjects: aging -- astrocyte -- Ca2+ -- JNK/SAPK -- mitochondria -- oxidative stress; Cells -- Aging -- Periodicals; 571.8783605
• DOI: 10.1111/acel.12523
• Languages: English
• ISSNs: 1474-9718

Abstract

Summary: 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 SDHC V69E mutation. 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‐H2 DCFDA‐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 Ca 2+ 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.