2013
DOI: 10.1111/jnc.12444
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Nucleic acid oxidation: an early feature of Alzheimer's disease

Abstract: Studies of oxidative damage during the progression of Alzheimer’s disease (AD) suggest its central role in disease pathogenesis. To investigate levels of nucleic acid oxidation in both early and late stages of AD, levels of multiple base adducts were quantified in nuclear and mitochondrial DNA from the superior and middle temporal gyri (SMTG), inferior parietal lobule (IPL), and cerebellum (CER) of age-matched normal control subjects, subjects with mild cognitive impairment, preclinical AD, late-stage AD, and … Show more

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Cited by 94 publications
(75 citation statements)
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“…Furthermore, significantly elevated levels of 8-hydroxyguaine and 8-hydroxyadenine observed in DC subjects were comparable to levels observed in both early and late stages of AD suggesting oxidation is a common feature of neurodegeneration, rather than an AD specific event. These findings are consistent with a previous study of nuclear and mitochondrial DNA nucleic acid oxidation in the same subject pool [51].…”
Section: Discussionsupporting
confidence: 94%
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“…Furthermore, significantly elevated levels of 8-hydroxyguaine and 8-hydroxyadenine observed in DC subjects were comparable to levels observed in both early and late stages of AD suggesting oxidation is a common feature of neurodegeneration, rather than an AD specific event. These findings are consistent with a previous study of nuclear and mitochondrial DNA nucleic acid oxidation in the same subject pool [51].…”
Section: Discussionsupporting
confidence: 94%
“…No significant correlations were detected between NP or NFT counts. Although multiple significant correlations between RNA adducts and specific pools of Aβ and Aβ in AD levels of multiple RNA lesions were also found to be significantly elevated in DC subjects whose levels of Aβ and Aβ were comparable to NC subjects, suggesting that the observed relationships are not a direct cause and effect consistent with previous reports that suggest nucleic acid oxidation is independent of amyloid deposition [51,52]. However, because the current study quantified median levels of RNA oxidation determined from bulk tissue, we were unable to address the hypothesis that intraneuronal non-oligomeric Aβ peptide may act as an antioxidant as supported by Nunomura et al [63,64] who found an inverse relationship between staining intensities of oxidized guanine and levels of intraneuronal non-oligomeric Aβ peptide and NFT tangle formation.…”
Section: Conflict Of Interestsupporting
confidence: 88%
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“…Oxidative stress causes nucleic acid lesions including DNA double and single strand breaks, base modifications, and deletions [61]. Previous studies have found evidence of DNA damage in postmortem brains of patients with Alzheimer’s disease [62], and the recent detection of DNA adducts in pre-clinical Alzheimer’s disease suggests that DNA damage is an early event in the course of disease [63]. Tau transgenic mice and flies have increased levels of pH2Ax or pH2Av, respectively, which are specific markers of DNA double strand breaks, and increased levels of p53, an effector of the DNA damage checkpoint [64].…”
Section: Mechanisms Of Tau Neurotoxicitymentioning
confidence: 99%
“…Some of the free radicals thus generated escape; rather than appropriately transporting their electron to the next molecule in the cascade, they abandon the inner membrane of the mitochondria and impose alterations on other macromolecules within the cell. These alterations are often detrimental: DNA/RNA oxidation may yield fragmentation and deficiencies in repair machinery 32, 33 ; oxidative modification of enzymes and metabolic signaling proteins may lead to metabolic impairments 34 ; and protein cross-linkages and impaired proteolysis network resulting from oxidative modification may render proteins insoluble and prone to aggregate abnormally 3537 .…”
Section: Neuronal Oxidative Stress: Sources and Vulnerabilitiesmentioning
confidence: 99%