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Mitochondrial Oxidative Stress Causes Hyperphosphorylation of Tau

  • 작성자한진
  • 작성일2007-06-25 18:01:45
  • 조회수3079
Age-related neurodegenerative disease has been mechanistically linked with mitochondrial dysfunction via damage from reactive oxygen species produced within the cell. We determined whether increased mitochondrial oxidative stress could modulate or regulate two of the key neurochemical hallmarks of Alzheimer's disease (AD): tau phosphorylation, and ß-amyloid deposition. Mice lacking superoxide dismutase 2 (SOD2) die within the first week of life, and develop a complex heterogeneous phenotype arising from mitochondrial dysfunction and oxidative stress. Treatment of these mice with catalytic antioxidants increases their lifespan and rescues the peripheral phenotypes, while uncovering central nervous system pathology. We examined sod2 null mice differentially treated with high and low doses of a catalytic antioxidant and observed striking elevations in the levels of tau phosphorylation (at Ser-396 and other phospho-epitopes of tau) in the low-dose antioxidant treated mice at AD-associated residues. This hyperphosphorylation of tau was prevented with an increased dose of the antioxidant, previously reported to be sufficient to prevent neuropathology. We then genetically combined a well-characterized mouse model of AD (Tg2576) with heterozygous sod2 knockout mice to study the interactions between mitochondrial oxidative stress and cerebral Aß load. We found that mitochondrial SOD2 deficiency exacerbates amyloid burden and significantly reduces metal levels in the brain, while increasing levels of Ser-396 phosphorylated tau. These findings mechanistically link mitochondrial oxidative stress with the pathological features of AD. Simon Melov1*, Paul A. Adlard2, Karl Morten1, Felicity Johnson1, Tamara R. Golden1, Doug Hinerfeld1, Birgit Schilling1, Christine Mavros2, Colin L. Masters2, Irene Volitakis2, Qiao-Xin Li2, Katrina Laughton2, Alan Hubbard3, Robert A. Cherny2, Brad Gibson1, Ashley I. Bush2,4* 1 Buck Institute for Age Research, Novato, California, United States of America, 2 Mental Health Research Institute of Victoria, and Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia, 3 School of Public Health, EHS/Biostatistics, University of California Berkeley, Berkeley, California, United States of America, 4 Department of Psychiatry, Massachusetts General Hospital, Charlestown, Massachusetts, United States of America (Journal article originally published in PLoS. Open Access.)
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400 한진교수 화의자의학상 수상 2023.01.05 관리자 2023.01.05 35
399 이온통로 학회 -Amy 포스터상 수상 2019.01.15 김형규 2019.01.15 2,577
398 센터 겸임교수 조성우 교수 - 한빛사 -JACC Vascular Imaging 2018.12.08 김형규 2018.12.08 2,718
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395 KORUS 2017 첨부파일 2017.06.21 김보현 2017.06.21 2,977
394 IMPACT 2016 심포지엄 개최 안내 첨부파일 2016.04.18 관리자 2016.04.18 3,984
393 IMPACT 2015 심포지엄 개최 안내 첨부파일 2015.04.20 서대윤 2015.04.20 2,864
392 2015 중점연구소 성과 전시회 첨부파일 2015.03.31 김형규 2015.03.31 2,455
391 Best Miso Award - 한진 2014.11.04 이정훈 2014.11.04 2,064
390 신진생리학자상 - 김형규 2014.10.29 이정훈 2014.10.29 1,808
389 대한생리학회 KJPP 인용상 - 김형규, 정승훈 2014.10.29 이정훈 2014.10.29 1,767
388 Best Presentation Award - 김형규 2014.09.29 이정훈 2014.09.29 1,002
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