TY - CHAP
T1 - Molecular pathophysiology of insulin depletion, mitochondrial dysfunction, and oxidative stress in Alzheimer’s disease brain
AU - Nakabeppu, Yusaku
N1 - Funding Information:
Fig. 3.2 8-oxoguanine accumulated in mitochondrial DNA of neuronal cells and nuclear DNA of microglia causes neurodegeneration. At the early stages of neurodegeneration with oxidative stress, high levels of 8-oxoG accumulate in mitochondrial DNA of neurons. As a result, the mitochondrial DNA is degraded in the process of BER initiated by MUTYH and is depleted; thus mitochondrial function is impaired. In such condition, synaptic dysfunction and neuronal degeneration can be induced. In the latter period, microglia are activated by eat-me signals such as nucleotides released from degenerating neurons. In activated microglia, high level of 8-oxoG accumulates in their nuclear DNA because ROS production is enhanced. Thereafter, DNA damage accumulates in nuclear DNA during the process of BER initiated by MUTYH.D NA damage accu - mulated in nuclear DNA of microglia induces activation of microglia, thus increasing production of cytokines and ROS, resulting in chronic microgliosis. Microgliosis exacerbates neuronal degeneration and neuronal loss by phagocytosis, as seen in AD brain Acknowledgments This work was partly supported by grants from the Japan Society for the Promotion of Science (KAKENHI: 1701391) and the Uehara Memorial Foundation. I thank all members in my lab and collaborators for their various comments and kind assistance.
Publisher Copyright:
© Springer Nature Singapore Pte Ltd. 2019.
PY - 2019/5/7
Y1 - 2019/5/7
N2 - Accumulating clinical data indicates that insulin resistance and diabetes mellitus (DM) are major risk factors for Alzheimer’s disease (AD); however, the exact mechanisms on how insulin resistance and DM act as risk factors for AD remain unclear. Recent progress in gene expression profiling of AD brains revealed that brain insulin production and insulin signaling are significantly impaired, indicating that AD brain exhibits a feature of brain diabetes with depletion of brain insulin, which causes mitochondrial dysfunction with increased oxidative stress, thereby increasing sensitivity to peripheral diabetes. Such diabetic condition in early stage of AD brain can be exacerbated by peripheral diabetes, namely, through hyperglycemia, hyperinsulinemia, or impaired insulin response. In this chapter, I reviewed mitochondrial dysfunction and oxidative stress in AD brain and discussed how those events are involved in AD pathogenesis.
AB - Accumulating clinical data indicates that insulin resistance and diabetes mellitus (DM) are major risk factors for Alzheimer’s disease (AD); however, the exact mechanisms on how insulin resistance and DM act as risk factors for AD remain unclear. Recent progress in gene expression profiling of AD brains revealed that brain insulin production and insulin signaling are significantly impaired, indicating that AD brain exhibits a feature of brain diabetes with depletion of brain insulin, which causes mitochondrial dysfunction with increased oxidative stress, thereby increasing sensitivity to peripheral diabetes. Such diabetic condition in early stage of AD brain can be exacerbated by peripheral diabetes, namely, through hyperglycemia, hyperinsulinemia, or impaired insulin response. In this chapter, I reviewed mitochondrial dysfunction and oxidative stress in AD brain and discussed how those events are involved in AD pathogenesis.
UR - http://www.scopus.com/inward/record.url?scp=85065663324&partnerID=8YFLogxK
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U2 - 10.1007/978-981-13-3540-2_3
DO - 10.1007/978-981-13-3540-2_3
M3 - Chapter
C2 - 31062324
AN - SCOPUS:85065663324
T3 - Advances in Experimental Medicine and Biology
SP - 27
EP - 44
BT - Advances in Experimental Medicine and Biology
PB - Springer
ER -
