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Oxidative Medicine and Cellular Longevity Volume 2020 ,2020-02-13
A Newly Synthesized Rhamnoside Derivative Alleviates Alzheimer’s Amyloid-β-Induced Oxidative Stress, Mitochondrial Dysfunction, and Cell Senescence through Upregulating SIRT3
Research Article
Yi Li 1 , 2 Jing Lu 1 Xin Cao 3 Hongwei Zhao 4 Longfei Gao 1 Peng Xia 5 Gang Pei 1 , 6 , 7
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DOI:10.1155/2020/7698560
Received 2019-09-24, accepted for publication 2020-01-10, Published 2020-02-13
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摘要

Oxidative stress-induced mitochondrial dysfunction and cell senescence are considered critical contributors to Alzheimer’s disease (AD), and oxidant/antioxidant imbalance has been a therapeutic target in AD. SIRT3 is a mitochondrial protein regulating metabolic enzyme activity by deacetylation and its downregulation is associated with AD pathology. In the present study, we showed that a newly synthesized rhamnoside derivative PL171 inhibited the generation of reactive oxidant species (ROS) induced by amyloid-β42 oligomers (Aβ42O), major AD pathological proteins. Moreover, the reduction of mitochondrial membrane potential (MMP) and the impairment of mitochondrial oxygen consumption triggered by Aβ42O were also prevented by PL171. Further experiments demonstrated that PL171 reduced the acetylation of mitochondrial proteins, and particularly the acetylation of manganese superoxide dismutase (MnSOD) and oligomycin-sensitivity-conferring protein (OSCP), two mitochondrial SIRT3 substrates, was suppressed by PL171. Mechanism studies revealed that PL171 upregulated SIRT3 and its upstream peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) under basal and Aβ42O-treated conditions. The inhibition of SIRT3 activity could eliminate the protective effects of PL171. Further, long-term treatment with Aβ42O increased the number of senescent neuronal cell, which was also alleviated by PL171 in a SIRT3-dependent manner. Taken together, our results indicated that PL171 rescued Aβ42O-induced oxidative stress, mitochondrial dysfunction, and cell senescence via upregulating SIRT3 and might be a potential drug candidate against AD.

授权许可

Copyright © 2020 Yi Li et al. 2020
This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

通讯作者

Gang Pei.State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China, ucas.ac.cn;Shanghai Key Laboratory of Signaling and Disease Research, Collaborative Innovation Center for Brain Science, School of Life Sciences and Technology, Tongji University, Shanghai, China, tongji.edu.cn;Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China, cas.cn.gpei@sibs.ac.cn

推荐引用方式

Yi Li,Jing Lu,Xin Cao,Hongwei Zhao,Longfei Gao,Peng Xia,Gang Pei. A Newly Synthesized Rhamnoside Derivative Alleviates Alzheimer’s Amyloid-β-Induced Oxidative Stress, Mitochondrial Dysfunction, and Cell Senescence through Upregulating SIRT3. Oxidative Medicine and Cellular Longevity ,Vol.2020(2020)

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