Nucleic acid oxidation: An early feature of Alzheimer's disease

Melissa A. Bradley-Whitman, Michael D. Timmons, Tina L. Beckett, Michael P. Murphy, Bert C. Lynn, Mark A. Lovell

Research output: Contribution to journalArticlepeer-review

87 Scopus citations

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 non-AD neurological disorders (diseased control; DC) using gas chromatography/mass spectrometry. Median levels of multiple DNA adducts in nuclear and mitochondrial DNA were significantly (p ≤ 0.05) elevated in the SMTG, IPL, and CER in multiple stages of AD and in DC subjects. Elevated levels of fapyguanine and fapyadenine in mitochondrial DNA suggest a hypoxic environment early in the progression of AD and in DC subjects. Overall, these data suggest that oxidative damage is an early event not only in the pathogenesis of AD but is also present in neurodegenerative diseases in general. Levels of oxidized nucleic acids in nDNA and mtDNA were found to be significantly elevated in mild cognitive impairment (MCI), preclinical Alzheimer's disease (PCAD), late-stage AD (LAD), and a pooled diseased control group (DC) of frontotemporal dementia (FTD) and dementia with Lewy bodies (DLB) subjects compared to normal control (NC) subjects. Nucleic acid oxidation peaked early in disease progression and remained elevated. The study suggests nucleic acid oxidation is a general event in neurodegeneration. Levels of oxidized nucleic acids in nDNA and mtDNA were found to be significantly elevated in mild cognitive impairment (MCI), preclinical Alzheimer's disease (PCAD), late-stage AD (LAD), and a pooled diseased control group (DC) of frontotemporal dementia (FTD) and dementia with Lewy bodies (DLB) subjects compared to normal control (NC) subjects. Nucleic acid oxidation peaked early in disease progression and remained elevated. The study suggests nucleic acid oxidation is a general event in neurodegeneration.

Original languageEnglish
Pages (from-to)294-304
Number of pages11
JournalJournal of Neurochemistry
Volume128
Issue number2
DOIs
StatePublished - Jan 2014

Funding

FundersFunder number
National Institutes of Health (NIH)5P01-AG05119, P30-AG028383
National Institute on AgingP30AG028383

    Keywords

    • Alzheimer's disease
    • mild cognitive impairment
    • mitochondrial DNA
    • neurodegenerative diseases
    • nuclear DNA
    • preclinical Alzheimer's disease

    ASJC Scopus subject areas

    • Biochemistry
    • Cellular and Molecular Neuroscience

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