Oxidatively modified nucleic acids in preclinical Alzheimer's disease (PCAD) brain

• Published in: Mechanisms of ageing and development Vol. 132; no. 8; pp. 443 - 448
• Main Authors: Lovell, Mark A., Soman, Sony, Bradley, Melissa A.
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Shannon Elsevier Ireland Ltd 01.08.2011; Elsevier
• Subjects: Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Autopsy; Base excision repair; Biological and medical sciences; Brain - metabolism; Brain - pathology; Development. Metamorphosis. Moult. Ageing; DNA - metabolism; DNA Damage; DNA Glycosylases - biosynthesis; DNA oxidation; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Enzymologic; Guanine - analogs & derivatives; Guanine - metabolism; Humans; Immunohistochemistry; Male; Nerve Tissue Proteins - biosynthesis; Oxidation-Reduction; Oxidative stress; Preclinical AD; RNA oxidation; RNA, Messenger - metabolism; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Oxidative stress; Preclinical AD; Base excision repair; DNA oxidation; RNA oxidation; Nervous system diseases; Senescence; RNA; Alzheimer disease; Cerebral disorder; Vertebrata; Mammalia; DNA; Central nervous system disease; Degenerative disease; Oxidation; Repair; Nucleic acid
• ISSN: 0047-6374; 1872-6216; 1872-6216
• DOI: 10.1016/j.mad.2011.08.003

► RNA associated 8-OHG is increased in PCAD hippocampus/parahippocampal gyri (HPG) compared to NC HPG. ► DNA associated 8-OHG is increased in PCAD HPG compared to NC HPG. ► Oxoguanine gylcosylase 1 is increased in PCAD although the difference was not statistically significant. Previous studies show increased oxidative DNA and RNA damage and diminished 8-oxoguanine glycosylase (OGG1) mediated base excision repair in vulnerable brain regions of mild cognitive impairment and late-stage Alzheimer's disease (LAD) subjects compared to normal control (NC) subjects. Recently, a preclinical stage of AD (PCAD) has been described in which subjects show no overt clinical manifestations of AD but demonstrate significant AD pathology at autopsy. To determine if DNA or RNA oxidation are significantly elevated in PCAD brain we quantified 8-hydroxyguanine (8-OHG) in sections of hippocampus/parahippocamapal gyri in PCAD and NC subjects using immunohistochemistry and confocal microscopy and in superior and middle temporal gyri (SMTG) using gas chromatography/mass spectrometry. To determine if increased DNA oxidation is associated with altered repair capacity, levels of OGG1 protein in HPG were measured by immunohistochemistry and levels of OGG1 mRNA were measured in SMTG using quantitative PCR. Results show significantly increased ( p < 0.05) 8-OHG immunostaining in DNA and RNA of PCAD HPG and significantly increased 8-OHG in PCAD SMTG. Quantification of OGG1 showed significantly elevated mRNA in PCAD SMTG and a trend toward elevated protein immunostaining in PCAD HPG. Overall, the data suggest oxidative damage to nucleic acids and a compensatory increase in OGG1 expression occur early in the pathogenesis of AD.