The DOI matches its Crossref record; 34 of the 34 references it cites were found in a registry or an index.
Mitochondrial Abnormalities in Alzheimer's Disease
Open accessAbstract
The finding that oxidative damage, including that to nucleic acids, in Alzheimer's disease is primarily limited to the cytoplasm of susceptible neuronal populations suggests that mitochondrial abnormalities might be part of the spectrum of chronic oxidative stress of Alzheimer's disease. In this study, we used in situ hybridization to mitochondrial DNA (mtDNA), immunocytochemistry of cytochrome oxidase, and morphometry of electron micrographs of biopsy specimens to determine whether there are mitochondrial abnormalities in Alzheimer's disease and their relationship to oxidative damage marked by 8-hydroxyguanosine and nitrotyrosine. We found that the same neurons showing increased oxidative damage in Alzheimer's disease have a striking and significant increase in mtDNA and cytochrome oxidase. Surprisingly, much of the mtDNA and cytochrome oxidase is found in the neuronal cytoplasm and in the case of mtDNA, the vacuoles associated with lipofuscin. Morphometric analysis showed that mitochondria are significantly reduced in Alzheimer's disease. The relationship shown here between the site and extent of mitochondrial abnormalities and oxidative damage suggests an intimate and early association between these features in Alzheimer's disease.
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In the citing paper
“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 Hirai et al., 2001
In the citing paper
“Considerable evidence suggests that mitochondrial dysfunction and oxidative stress contribute to the progression of Alzheimer’s disease (AD).”
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 Hirai et al., 2001
In the citing paper
“MtDNA from AD subject brains exhibits excess oxidative damage and deletions [47, 102-105].”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [47]
In the citing paper
“In aggregate, AD subject brains and blood cells contain less PCR-amplifiable mtDNA [47, 105, 109-111].”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [47]
In the citing paper
“Existing data suggest mitochondrial function declines throughout much of adulthood and that adaptive changes, at least initially, mitigate this decline [47, 80-82].”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [47]
In the citing paper
“The mitochondria, are a source of free radicals and ROS, as well as being susceptible to ROS damage.33”
From Bacopa monnieri (L.) wettst. Extract protects against glutamate toxicity and increases the longevity of Caenorhabditis elegans (2020) · cites this paper as [33]
In the citing paper
“Mitochondrial damage in neurons is considered to be a risk factor for neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease.33,35”
From Bacopa monnieri (L.) wettst. Extract protects against glutamate toxicity and increases the longevity of Caenorhabditis elegans (2020) · cites this paper as [33]
In the citing paper
“Mitochondrial mass, or at least parameters related to it, also appear to change during brain aging. Studies are limited, but overall suggest that with advancing age mitochondrial mass increases or attempts to increase.”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [111]
In the citing paper
“Most studies report the number of intact, normal appearing mitochondria declines [111, 138].”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [111]
In the citing paper
“AD subject hippocampal neurons, however, contain more degrading or degraded mitochondria than control subject hippocampal neurons [111].”
From Brain aging, Alzheimer's disease, and mitochondria (2011) · cites this paper as [111]
In the citing paper
“These results confirmed that mtDNA is a target of oxidative damage and that the increased damage to DNA contributes to AD and the neurodegenerative process [51,53].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [53]
In the citing paper
“Hirai et al. have demonstrated that oxidative damage marked by 8-OHdG and nitrotyrosine occurs in the neurons of AD patients. Morphometric analysis showed a reduction of mitochondria in these same neurons and an accumulation of mtDNA and mitochondrial proteins [53].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [53]
In the citing paper
“These abnormalities are found in neurons lacking neurofibrillary tangles, suggesting that mitochondrial abnormalities are one of the earliest pathological changes in AD.”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [53]
In the citing paper
“In the AD brain, mitochondria can be sources of ROS and also the target of OS, especially mitochondrial DNA (mtDNA) is susceptible to oxidative damage [19,53,63].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [53]
In the citing paper
“Oxidation of DNA and RNA produced by ROS also occurs in AD [50,51,52,53].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [53]
Citations
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MethodWidespread Peroxynitrite-Mediated Damage in Alzheimer’s Disease
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Self-citation
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“Accumulation of damages to mtDNA content and integrity can give rise to mitochondrial morphology abnormalities (Hirai et al, 2001).”
Mitochondrial Function and Neurodegenerative Diseases
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Metadata
- Authors
- Hirai, K., Aliev, G., Nunomura, A., Fujioka, H., Russell, R. L., Atwood, C. S., Johnson, A. B., Kress, Y., Vinters, H. V., Tabaton, M., Shimohama, S., Cash, A. D., Siedlak, S. L., Harris, P. L. R., Jones, P. K., Petersen, R. B., Perry, G., & Smith, M. A.
- Affiliations
- Takeda (Japan) (JP)
- Asahikawa Medical University (JP)
- Albert Einstein College of Medicine (US)
- University of California, Los Angeles (US)
- University of Genoa (IT)
- Kyoto University (JP)
- Case Western Reserve University (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2001-05-01
- Volume
- 21
- Issue
- 9
- Pages
- 3017-3023
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6762571
- OpenAlex
- W2165427528
- Cited by
- 1,367
- References
- 34
- Citations by year
- 2026: 29 · 2025: 32 · 2024: 41 · 2023: 52 · 2022: 58 · 2021: 69 · 2020: 78 · 2019: 50 · 2018: 60 · 2017: 59 · 2016: 66 · 2015: 47 · 2014: 61 · 2013: 55 · 2012: 74
- FWCI
- 11.75
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Health Assistance Foundation
- National Institutes of Health (5r01ag009287-08, AG09287)
- National Institute on Aging (P50AG016570, P50-AG 16570, AG-14249, R01AG014249, AG 09287)
- National Institute of Neurological Disorders and Stroke (NS 38648, R01NS038648)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, mitochondrial abnormalities, oxidative stress, mitochondrial DNA, cytochrome c oxidase, 8-hydroxyguanosine, nitrotyrosine, lipofuscin, neuronal cytoplasm, oxidative DNA damage
- MeSH terms
- Adolescent, Adult, Aged, Aged, 80 and over, Alzheimer Disease, Cerebellum, Child, Child, Preschool, Electron Transport Complex IV, DNA, Mitochondrial, Frontal Lobe, Guanosine, Hippocampus, Humans, Immunohistochemistry, Microscopy, Electron, Middle Aged, Mitochondria, Neurons, Temporal Lobe, Tyrosine, In Situ Hybridization, Oxidative Stress
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