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Cited by 940Alzheimer's disease research and treatmentsMitochondrial Function and PathologyDementia and Cognitive Impairment Research

Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease

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Yao, Jia, Irwin, Ronald W., Zhao, Liqin, Nilsen, Jon, Hamilton, Ryan T., Brinton, Roberta Diaz·2009·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0903563106PMC PMC2732886
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Abstract

Mitochondrial dysfunction has been proposed to play a pivotal role in neurodegenerative diseases, including Alzheimer's disease (AD). To address whether mitochondrial dysfunction precedes the development of AD pathology, we conducted mitochondrial functional analyses in female triple transgenic Alzheimer's mice (3xTg-AD) and age-matched nontransgenic (nonTg). Mitochondrial dysfunction in the 3xTg-AD brain was evidenced by decreased mitochondrial respiration and decreased pyruvate dehydrogenase (PDH) protein level and activity as early as 3 months of age. 3xTg-AD mice also exhibited increased oxidative stress as manifested by increased hydrogen peroxide production and lipid peroxidation. Mitochondrial amyloid beta (Aβ) level in the 3xTg-AD mice was significantly increased at 9 months and temporally correlated with increased level of Aβ binding to alcohol dehydrogenase (ABAD). Embryonic neurons derived from 3xTg-AD mouse hippocampus exhibited significantly decreased mitochondrial respiration and increased glycolysis. Results of these analyses indicate that compromised mitochondrial function is evident in embryonic hippocampal neurons, continues unabated in females throughout the reproductive period, and is exacerbated during reproductive senescence. In nontransgenic control mice, oxidative stress was coincident with reproductive senescence and accompanied by a significant decline in mitochondrial function. Reproductive senescence in the 3xTg-AD mouse brain markedly exacerbated mitochondrial dysfunction. Collectively, the data indicate significant mitochondrial dysfunction occurs early in AD pathogenesis in a female AD mouse model. Mitochondrial dysfunction provides a plausible mechanistic rationale for the hypometabolism in brain that precedes AD diagnosis and suggests therapeutic targets for prevention of AD.

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  • Mitochondrial function and oxidative stress have been fully characterized only in female 3xTg-AD mice.

    “Furthermore, mitochondrial function and oxidative stress have been fully characterized only in female 3xTg-AD mice (Yao et al., 2009).”

    From The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease (2011) · cites this paper as Yao et al., 2009

    The Results and Discussion (page not provided) characterize mitochondrial function and oxidative stress in female 3xTg-AD mice. The paper does not establish the broader claim that these measures had been fully characterized only in females. (LLM, conf=0.86)

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  • Alterations in glucose metabolism and mitochondrial energetics occur along with accumulation of oxidative damage before the cardinal signs of Alzheimer's disease pathogenesis in the brains of transgenic animal models and patients.

    “Extensive evidence indicates that alterations in glucose metabolism and mitochondrial energetics occur along with the accumulation of oxidative damage before the cardinal signs of AD pathogenesis in the brains of transgenic animal models and patients (Hoyer, 1996; Hirai et al., 2001; Rinaldi et al., 2003; Butterfield et al., 2006; Lin and Beal, 2006; Sultana et al., 2006a,b; Mosconi et al., 2008a;”

    From The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease (2011) · cites this paper as Yao et al., 2009

    The Results and Discussion report early mitochondrial dysfunction, altered glycolysis, and oxidative stress in female 3xTg-AD mice; the Discussion says mitochondrial dysfunction precedes plaque formation. It also describes reduced glucose use as an early finding in people at risk of AD, but does not establish that oxidative damage precedes the cardinal signs of AD in patients. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The mitochondrial dysfunction evident in 3xTg-AD mice recapitulates multiple parameters found in MCI and early AD patients, including decreased mitochondrial bioenergetics, increased oxidative stress, and increased mitochondrial Aβ load.

    “The mitochondrial dysfunction evident in these mice also recapitulates multiple parameters found in MCI and early AD patients, including decreased mitochondrial bioenergetics, increased oxidative stress, and increased mitochondrial Aβ load (Billings et al., 2005; Yao et al., 2009).”

    From The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease (2011) · cites this paper as Yao et al., 2009

    The Discussion states that female 3xTg-AD mice recapitulate decreased mitochondrial bioenergetics, increased oxidative stress, and increased mitochondrial amyloid load described in human AD patients. It also discusses MCI in connection with early bioenergetic changes, but does not establish that all three parameters occur specifically in MCI and early AD patients. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Modification of mitochondrial enzymes and components of the respiratory chain by RS may contribute to impaired glucose metabolism in preclinical AD subjects.

    “Modification of mitochondrial enzymes and components of the respiratory chain by RS may contribute to impaired glucose metabolism found in preclinical AD subjects”

    From The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease (2011) · cites this paper as Yao et al., 2009

    The Discussion reports that oxidative damage to mitochondrial proteins impairs oxidative phosphorylation, and links reduced PDH and COX activity to altered glucose metabolism in AD-model mice. It also cites decreased glucose uptake in people at increased risk of AD. It does not establish that reactive-species modification of respiratory-chain components causes the impaired glucose metabolism observed in preclinical human subjects. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Aβ deposition and early cognitive impairment are preceded by mitochondrial dysfunction and increased oxidative stress in 3xTg-AD mouse brains.

    “Aβ deposition and early cognitive impairment are preceded by mitochondrial dysfunction and increased oxidative stress in 3xTg-AD mouse brains (Resende et al., 2008; Yao et al., 2009).”

    From The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease (2011) · cites this paper as Yao et al., 2009

    The Results report early mitochondrial dysfunction and increased oxidative stress in female 3xTg-AD mice; the Discussion states that mitochondrial dysfunction precedes plaque formation. The paper does not establish that these changes precede early cognitive impairment, and its timing claim concerns plaques rather than all Aβ accumulation. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

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Authors
Yao, J., Irwin, R. W., Zhao, L., Nilsen, J., Hamilton, R. T., & Brinton, R. D.
Affiliations
  • University of Southern California (US)
  • Department of Pharmacology and Pharmaceutical Sciences and Program in Neuroscience, Pharmaceutical Sciences Center, University of Southern California, Los Angeles, CA 90033
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2009-08-25
Volume
106
Issue
34
Pages
14670-14675
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0903563106
PMC
PMC2732886
OpenAlex
W2119983609
Cited by
940
References
3
Citations by year
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FWCI
33.42
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institute on Aging (AG026572, R01AG032236, T32AG000093, T32-AG000093-24/25, P01AG026572)
  • National Institute of Mental Health (R01MH067159, 1R01 MH67159-01)
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
Alzheimer's disease, mitochondrial dysfunction, mitochondrial respiration, pyruvate dehydrogenase, oxidative stress, hydrogen peroxide, lipid peroxidation, amyloid-beta, alcohol dehydrogenase, reproductive aging, female brain, hippocampal neurons, glycolysis, brain hypometabolism, 3xTg-AD mice, neurodegeneration
MeSH terms
Alzheimer Disease, Amyloid, Animals, Brain, Electron Transport Complex IV, Disease Models, Animal, Female, Hippocampus, Humans, Hydrogen Peroxide, Immunohistochemistry, Lipid Peroxides, Mice, Inbred C57BL, Mice, Inbred Strains, Mice, Transgenic, Mitochondria, Oxygen Consumption, Time Factors, Blotting, Western, Lipid Peroxidation, Oxidative Stress, Pyruvate Dehydrogenase (Lipoamide), Mice

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