ATOX1 overexpression mitigates copper homeostasis in microglia:Implications for Alzheimer''s disease therapyOA
Copper(Cu^(2+))is a known contributor to the pathogenesis of Alzheimer''s disease(AD).However,it is uncertain whether proteins regulating copper homeostasis affect Cu^(2+)in microglia.Antioxidant protein 1(ATOX1)plays a key role in Cu^(2+)homeostasis,oxidative stress,and cell protection.Despite its critical functions,the role of ATOX1 in AD pathology remains poorly defined.This study aims to examine the effects of ATOX1 on oxidative stress,apoptosis,and neuroinflammation in microglia by modulating Cu^(2+)homeostasis.In vivo,a 5×FAD mouse model was used to investigate the localization and expression of ATOX1 in AD by immunofluorescence and three-dimensional reconstruction.The Aβ1-42 oligomer was used to establish an AD model in vitro.The role of ATOX1 in Cu^(2+)homeostasis regulation in microglia was further studied using co-immunoprecipitation,Western blotting,quantitative real-time PCR,and spectrophotometry.A reduction in ATOX1 expression was noted in Aβ-plaques-associated microglia compared with normal microglia.Cu^(2+)levels were elevated in the in vitro AD model,and ATOX1 directly regulated copper homeostasis via P1B-ATPase(ATP7B)in microglia.Excessive Cu^(2+)induced oxidative stress,neuroinflammation,and apoptosis.Overexpression of ATOX1 alleviated this neurotoxicity,indicating its potential to alleviate oxidative stress,cell apoptosis,and neuroinflammation in AD.ATOX1 overexpression offers protective effects on microglia through Cu^(2+)homeostasis,which may lead to potential therapeutic strategies for AD.
Fuxin Zhong;Jiani Wu;Zhangjing Deng;Wuhan Yu;Jiaqi Song;Yingxi Chen;Weihua Yu;Yang Lu
Department of Geriatrics,The First Affiliated Hospital of Chongqing Medical University,Chongqing 400016,China Key Laboratory of Major Brain Disease and Aging Research(Ministry of Education),Chongqing Medical University,Chongqing 400014,China Institute for Brain Science and Disease,Chongqing Medical University,Chongqing 400016,ChinaDepartment of Geriatrics,The First Affiliated Hospital of Chongqing Medical University,Chongqing 400016,China Key Laboratory of Major Brain Disease and Aging Research(Ministry of Education),Chongqing Medical University,Chongqing 400014,China Institute for Brain Science and Disease,Chongqing Medical University,Chongqing 400016,ChinaDepartment of Geriatrics,The First Affiliated Hospital of Chongqing Medical University,Chongqing 400016,China Key Laboratory of Major Brain Disease and Aging Research(Ministry of Education),Chongqing Medical University,Chongqing 400014,China Institute for Brain Science and Disease,Chongqing Medical University,Chongqing 400016,ChinaDepartment of Geriatrics,The First Affiliated Hospital of Chongqing Medical University,Chongqing 400016,China Key Laboratory of Major Brain Disease and Aging Research(Ministry of Education),Chongqing Medical University,Chongqing 400014,China Institute for Brain Science and Disease,Chongqing Medical University,Chongqing 400016,ChinaInstitute of Neuroscience,Department of Human Anatomy,Chongqing Medical University,Chongqing 400016,ChinaInstitute of Neuroscience,Department of Human Anatomy,Chongqing Medical University,Chongqing 400016,ChinaInstitute of Neuroscience,Department of Human Anatomy,Chongqing Medical University,Chongqing 400016,ChinaDepartment of Geriatrics,The First Affiliated Hospital of Chongqing Medical University,Chongqing 400016,China Key Laboratory of Major Brain Disease and Aging Research(Ministry of Education),Chongqing Medical University,Chongqing 400014,China Institute for Brain Science and Disease,Chongqing Medical University,Chongqing 400016,China
医药卫生
Alzheimer’s diseaseATOX1CopperMicrogliaOxidative stress
《Genes & Diseases》 2026 (4)
P.677-689,13
supported by grants from the Chongqing Talent Plan(China)(No.cstc2022ycjh-bgzxm0184)the Key Project of Science and Technology Research Program of Chongqing Municipal Education Commission(China)(No.KJZD-K202200405)the Innovation Project for Doctoral Students at The First Affiliated Hospital of Chongqing Medical University(China)(No.CYYY-BSYJSCXXM-202320)the Chongqing Medical Key Discipline and Regional Medical Key Discipline Development Project(China)(0201[2023]No.160202412).
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