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Marked Changes in Mitochondrial DNA Deletion Levels in Alzheimer Brains
Abstract
Levels of the common 4977 nucleotide pair (np) mitochondrial DNA (mtDNA) deletion (mtDNA4977) were quantitated in the cortex, putamen, and cerebellum of patients with Alzheimer disease (AD) and compared to age-matched controls. Although cerebellum deletion levels were comparably low in AD patients and controls of all ages, cortical deletion levels were clearly different. The levels of mtDNA deletions in control brains started low, but rose markedly after age 75, while those of AD patients started high and declined to low levels by age 80. Choosing age 75 to arbitrarily delineate between younger and older subjects, younger patients had 15 times more mtDNA deletions than younger controls, while older patients had one-fifth the deletion level of older controls. Younger AD patients also had fourfold more deletions than older AD patients. These results support the hypothesis that OXPHOS defects resulting from somatic mtDNA mutations may play a role in AD pathophysiology.
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“which has been described in an AD brain [169,170] in which base deletions correlate with complex IV deficiency in an AD hippocampus [171].”
From Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease (2020) · cites this paper as [169]
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 [103]
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The Free Radical Theory of Aging Matures
BECKMAN, K. B., & AMES, B. N. (1998) · Physiological Reviews · doi:10.1152/physrev.1998.78.2.547 · Cited by 3,879
Wallace, D. C. (2005) · Annual Review of Genetics · doi:10.1146/annurev.genet.39.110304.095751 · Cited by 3,185
“In the brains of AD patients who died prior to age 75, the 5-kb deletion is increased on average 15-fold, whereas in the brains of patients who died after age 75, the 5-kb deletion is present at one fifth the level of that in control brains (40).”
BackgroundSelf-citationMitochondrial diseases in man and mouse
Wallace, D. C. (1999) · Science · doi:10.1126/science.283.5407.1482 · Cited by 3,060
Self-citationOxidative stress and mitochondrial dysfunction in Alzheimer’s disease
Wang, X., Wang, W., Li, L., Perry, G., Lee, H.-G., & Zhu, X. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.10.015 · Cited by 1,357
“Elevated levels of sporadic mutations in the mtDNA including the most common 5-kb deletion were demonstrated in the brain of AD patients [101,102].”
Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: Recent advances.
Wang, W., Zhao, F., Ma, X., Perry, G., & Zhu, X. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00376-6 · Cited by 1,274
Metadata
- Authors
- Corral-Debrinski, M., Horton, T., Lott, M. T., Shoffner, J. M., McKee, A. C., Beal, M. F., Graham, B. H., & Wallace, D. C.
- Affiliations
- Harvard University (US)
- Venue
- Genomics
- Publisher
- Elsevier BV
- Published
- 1994-09
- Volume
- 23
- Issue
- 2
- Pages
- 471-476
- ISSN
- 0888-7543 (ISSN-L)
- OpenAlex
- W2060626022
- Cited by
- 309
- References
- 0
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 11 · 2023: 8 · 2022: 24 · 2021: 6 · 2020: 15 · 2019: 13 · 2018: 13 · 2017: 8 · 2016: 4 · 2015: 9 · 2014: 8 · 2013: 13 · 2012: 10
- FWCI
- 2.15
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Genomics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5f32ca009329-02)
- National Institute on Aging (P30AG010130, 1P30AG10130)
- National Cancer Institute (CA09329)
- National Center for Research Resources (M01-RR00039, M01RR000039)
- 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
- mitochondrial DNA deletions, Alzheimer's disease, somatic mtDNA mutations, brain aging, cortical mitochondria, putamen, cerebellum
- MeSH terms
- Age Factors, Aged, Aged, 80 and over, Alzheimer Disease, Cerebellum, Cerebral Cortex, DNA Damage, DNA, Mitochondrial, Female, Humans, Male, Middle Aged, Oxidative Phosphorylation, Putamen, Tissue Distribution, Sequence Deletion
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