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Cited by 363Alzheimer's disease research and treatmentsMitochondrial Function and PathologyDementia and Cognitive Impairment Research

Mitochondrial Oxidative Stress Causes Hyperphosphorylation of Tau

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Melov, Simon, Adlard, Paul A., Morten, Karl, Johnson, Felicity, Golden, Tamara R., Hinerfeld, Doug, Schilling, Birgit, Mavros, Christine +8 more·2007·PLoS ONE
DOI 10.1371/journal.pone.0000536PMC PMC1888726
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Abstract

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 beta-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.

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  • In mice, mitochondrial deficiency of superoxide dismutase is associated with hyperphosphorylation of tau and exacerbation of amyloid burden.

    “In mice, mitochondrial deficiency of superoxide dismutase was associated with hyperphosphorylation of tau and exacerbation of amyloid burden (Melov et al., 2007).”

    From Iron, Oxidative Stress and Health (2012) · cites this paper as Melov et al., 2007

  • Mitochondrial dysfunction leads to tau phosphorylation and Aβ production.

    “Increased stress signaling may also dysregulate mitochondrial function, which also leads to tau phosphorylation149 and Aβ production150 (Fig. 5, orange).”

    From Stress weakens prefrontal networks: molecular insults to higher cognition (2015) · cites this paper as [150]

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Authors
Melov, S., Adlard, P. A., Morten, K., Johnson, F., Golden, T. R., Hinerfeld, D., Schilling, B., Mavros, C., Masters, C. L., Volitakis, I., Li, Q.-X., Laughton, K., Hubbard, A., Cherny, R. A., Gibson, B., & Bush, A. I.
Affiliations
  • Buck Institute for Research on Aging (US)
  • Mental Health Research Institute (AU)
  • University of California, Berkeley (US)
Corresponding author
  • Melov, Simon
  • Bush, Ashley I.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2007-06-20
Volume
2
Issue
6
Pages
e536
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0000536
PMC
PMC1888726
OpenAlex
W2006717582
Cited by
363
References
12
Citations by year
2026: 19 · 2025: 14 · 2024: 27 · 2023: 19 · 2022: 25 · 2021: 27 · 2020: 21 · 2019: 19 · 2018: 13 · 2017: 15 · 2016: 11 · 2015: 23 · 2014: 23 · 2013: 17 · 2012: 19
FWCI
10.06
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by)
Funders
  • Ellison Medical Foundation
  • American Health Assistance Foundation
  • National Institutes of Health
  • Medical Research Council
  • Australian Research Council
  • National Health and Medical Research Council
  • National Institute on Aging (AG 12686, P01AG025901, P01 AG25901, AG18679, R01AG012686, R01AG018679)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
mitochondrial oxidative stress, tau hyperphosphorylation, Alzheimer's disease, manganese superoxide dismutase, Sod2 knockout mice, catalytic antioxidants, amyloid-beta deposition, mitochondrial dysfunction, reactive oxygen species, Tg2576 mice
MeSH terms
Superoxide Dismutase 2, Animals, Antioxidants, Female, Immunoenzyme Techniques, Male, Metals, Mice, Inbred C57BL, Mitochondria, Phosphorylation, Superoxide Dismutase, Blotting, Western, tau Proteins, Reactive Oxygen Species, Mice, Knockout, Oxidative Stress, Spectrometry, Mass, Electrospray Ionization, Immunoprecipitation, Mice, Plaque, Amyloid

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