Markers of oxidative damage to lipids, nucleic acids and proteins and antioxidant enzymes activities in Alzheimer’s disease brain: A meta-analysis in human pathological specimens
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Oxidative stress and decreased cellular responsiveness to oxidative stress are thought to influence brain aging and Alzheimer's disease, but the specific patterns of oxidative damage and the underlying mechanism leading to this damage are not definitively known. The objective of this study was to define the pattern of changes in oxidative-stress related markers by brain region in human Alzheimer's disease and mild cognitive impairment brain tissue. Observational case-control studies were identified from systematic queries of PubMed, ISI Web of Science and Scopus databases and studies were evaluated with appropriate quality measures. The data was used to construct a region-by-region meta-analysis of malondialdehyde, 4-hydroxynonenal, protein carbonylation, 8-hydroxyguanine levels and superoxide dismutase, glutathione peroxidase, glutathione reductase and catalase activities. We also evaluated ascorbic acid, tocopherol, uric acid and glutathione levels. The analysis was complicated in several cases by publication bias and/or outlier data. We found that malondialdehyde levels were slightly increased in the temporal and occipital lobes and hippocampus, but this analysis was significantly impacted by publication bias. 4-hydroxynonenal levels were unchanged in every brain region. There was no change in 8-hydroxyguanine level in any brain region and protein carbonylation levels were unchanged except for a slight increase in the occipital lobe. Superoxide dismutase, glutathione peroxidase and reductase and catalase activities were not decreased in any brain region. There was limited data reporting non-enzymatic antioxidant levels in Alzheimer's disease brain, although glutathione and tocopherol levels appear to be unchanged. Minimal quantitative data is available from brain tissue from patients with mild cognitive impairment. While there is modest evidence supporting minor regional changes in markers of oxidative damage, this analysis fails to identify a consistent pattern of pro-oxidative changes and accumulation of oxidative damage in bulk tissue analysis in the setting of Alzheimer's disease, as has been widely reported.
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Oxidative damage may be linked to the genetic risk of AD, and in this view more relevant in patients carrying the APOE ε4 allele.
“Besides, oxidative damage may be linked to the genetic risk of AD, and in this view more relevant in patients carrying the APOE ε4 allele [169].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [169]
Despite failure of studies on oxidative damage products in AD to reveal reliable marker, oxidative damage can be localized to mitochondria in AD brain and ROS may act as second messenger, initiating a downstream signaling pathway to face up the alteration in the redox balance.
“Despite the failure of studies on oxidative damage products in AD to reveal, till now, one or more reliable marker, oxidative damage can be localized to mitochondria in AD brain and ROS may act as second messenger, initiating a downstream signaling pathway to face up the alteration in the redox balance [169].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [169]
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1 retracted
Ghribi, O., Golovko, M. Y., Larsen, B., Schrag, M., & Murphy, E. J. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04079.x · Cited by 122 · see citing works
Self-citationRetractedOxidants, oxidative stress and the biology of ageing
Finkel, T., & Holbrook, N. J. (2000) · Nature · doi:10.1038/35041687 · Cited by 9,413 · see citing works
Ayala, A., Muñoz, M., & Argüelles, S. (2014) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2014/360438 · Cited by 6,561 · see citing works
A Controlled Trial of Selegiline, Alpha-Tocopherol, or Both as Treatment for Alzheimer's Disease
Sano, M., Ernesto, C., Thomas, R. G., Klauber, M. R., Schafer, K., Grundman, M., Woodbury, P., Growdon, J., Cotman, C. W., Pfeiffer, E., et al. (1997) · New England Journal of Medicine · doi:10.1056/nejm199704243361704 · Cited by 2,380 · see citing works
Oxidative Damage Is the Earliest Event in Alzheimer Disease
Nunomura, A., Perry, G., Aliev, G., Hirai, K., Takeda, A., Balraj, E. K., Jones, P. K., Ghanbari, H., Wataya, T., Shimohama, S., et al. (2001) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/60.8.759 · Cited by 1,885 · see citing works
Self-citationVitamin E and Donepezil for the Treatment of Mild Cognitive Impairment
Petersen, R. C., Thomas, R. G., Grundman, M., Bennett, D., Doody, R., Ferris, S., Galasko, D., Jin, S., Kaye, J., Levey, A., et al. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa050151 · Cited by 1,844 · see citing works
The case of the misleading funnel plot
Lau, J., Ioannidis, J. P. A., Terrin, N., Schmid, C. H., & Olkin, I. (2006) · BMJ · doi:10.1136/bmj.333.7568.597 · Cited by 1,766 · see citing works
The emerging field of lipidomics
Wenk, M. R. (2005) · Nature Reviews Drug Discovery · doi:10.1038/nrd1776 · Cited by 1,325 · see citing works
Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease
Mecocci, P., MacGarvey, U., & Beal, M. F. (1994) · Annals of Neurology · doi:10.1002/ana.410360510 · Cited by 1,037 · see citing works
Ascorbate regulation and its neuroprotective role in the brain
Rice, M. E. (2000) · Trends in Neurosciences · doi:10.1016/s0166-2236(99)01543-x · Cited by 835 · see citing works
Midlife vascular risk factors and late-life mild cognitive impairment: A population-based study
Kivipelto, M., Helkala, E.-L., Hänninen, T., Laakso, M. P., Hallikainen, M., Alhainen, K., Soininen, H., Tuomilehto, J., & Nissinen, A. (2001) · Neurology · doi:10.1212/wnl.56.12.1683 · Cited by 717 · see citing works
Increased Nuclear DNA Oxidation in the Brain in Alzheimer's Disease
Gabbita, S. P., Lovell, M. A., & Markesbery, W. R. (1998) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1998.71052034.x · Cited by 479 · see citing works
Gowrishankar, S., Yuan, P., Wu, Y., Schrag, M., Paradise, S., Grutzendler, J., De Camilli, P., & Ferguson, S. M. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1510329112 · Cited by 406 · see citing works
Self-citationGalasko, D. R., Peskind, E., Clark, C. M., Quinn, J. F., Ringman, J. M., Jicha, G. A., Cotman, C., Cottrell, B., Montine, T. J., Thomas, R. G., et al. (2012) · Archives of Neurology · doi:10.1001/archneurol.2012.85 · Cited by 377 · see citing works
Brain Glutathione Levels – A Novel Biomarker for Mild Cognitive Impairment and Alzheimer’s Disease
Mandal, P. K., Saharan, S., Tripathi, M., & Murari, G. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2015.04.005 · Cited by 339 · see citing works
Oxidative stress in blood in Alzheimer's disease and mild cognitive impairment: A meta-analysis
Schrag, M., Mueller, C., Zabel, M. K., Crofton, A. R., Kirsch, W. M., Ghribi, O., Squitti, R., & Perry, G. L. (2013) · Neurobiology of Disease · doi:10.1016/j.nbd.2013.07.005 · Cited by 335 · see citing works
Self-citationRegulation of the transcription factors NF-κB and AP-1 by redox changes
Meyer, M., Pahl, H. L., & Baeuerle, P. A. (1994) · Chemico-Biological Interactions · doi:10.1016/0009-2797(94)90029-9 · Cited by 310 · see citing works
Schrag, M., McAuley, G. A., Pomakian, J., Jiffry, A., Tung, S., Mueller, C., Vinters, H. V., Haacke, E. M., Holshouser, B. A., Kido, D. K., et al. (2009) · Acta Neuropathologica · doi:10.1007/s00401-009-0615-z · Cited by 287 · see citing works
Self-citationIncreased oxidative damage in nuclear and mitochondrial DNA in mild cognitive impairment
Wang, J., Markesbery, W. R., & Lovell, M. A. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2005.03615.x · Cited by 260 · see citing works
The Effect of Borderline Diabetes on the Risk of Dementia and Alzheimer’s Disease
Xu, W., Qiu, C., Winblad, B. G., & Fratiglioni, L. (2006) · Diabetes · doi:10.2337/db06-0879 · Cited by 218 · see citing works
Mandal, P. K., Tripathi, M., & Sugunan, S. (2011) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2011.11.047 · Cited by 199 · see citing works
Evidence of an oxidative challenge in the Alzheimer's brain
Balázs, L., & Leon, M. (1994) · Neurochemical Research · doi:10.1007/bf00965146 · Cited by 196 · see citing works
Oxidative Insults Are Associated with Apolipoprotein E Genotype in Alzheimer's Disease Brain
Ramassamy, C., Averill‐Bates, D. A., Beffert, U., Théroux, L., Lussier‐Cacan, S., Cohn, J. S., Christen, Y., Schoofs, A. R., Davignon, J., & Poirier, J. (2000) · Neurobiology of Disease · doi:10.1006/nbdi.1999.0273 · Cited by 194 · see citing works
Colacurcio, D. J., Pensalfini, A., Jiang, Y., & Nixon, R. A. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2017.10.001 · Cited by 167 · see citing works
Dedeoglu, A., Choi, J., Cormier, K., Kowall, N. W., & Jenkins, B. G. (2004) · Brain Research · doi:10.1016/j.brainres.2004.02.079 · Cited by 158 · see citing works
Down syndrome and dementia: A randomized, controlled trial of antioxidant supplementation
Lott, I. T., Doran, E., Nguyen, V. Q., Tournay, A., Head, E., & Gillen, D. L. (2011) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.34114 · Cited by 136 · see citing works
Kook, S.-Y., Lee, K.-M., Kim, Y., Cha, M.-Y., Kang, S., Baik, S., Lee, H., Park, R., & Mook‐Jung, I. (2014) · Cell Death and Disease · doi:10.1038/cddis.2014.26 · Cited by 127 · see citing works
He, X., Kim, M., Kim, S., Yi, S., Rhee, Y., Kim, T., Lee, E.-H., Park, C., Dixit, S., Harrison, F. E., et al. (2014) · Stem Cells · doi:10.1002/stem.1932 · Cited by 119 · see citing works
Self-citationRukhsana Sultana, A., Piroddi, M., Galli, F., & Butterfield, D. A. (2008) · Neurochemical Research · doi:10.1007/s11064-008-9593-0 · Cited by 115 · see citing works
Karelson, E., Bogdanović, N., Garlind, A., Winblad, B. G., Zilmer, K., Kullisaar, T., Vihalemm, T., Kairane, C., & Zilmer, M. (2001) · Neurochemical Research · doi:10.1023/a:1010942929678 · Cited by 114 · see citing works
Nucleic acid oxidation: an early feature of Alzheimer's disease
Bradley‐Whitman, M. A., Timmons, M. D., Beckett, T. L., Murphy, M. P., Lynn, B. C., & Lovell, M. A. (2014) · Journal of Neurochemistry · doi:10.1111/jnc.12444 · Cited by 112 · see citing works
Murakami, K., Murata, N., Ozawa, Y., Kinoshita, N., Irie, K., Shirasawa, T., & Shimizu, T. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-101971 · Cited by 108 · see citing works
Individual Case Analysis of Postmortem Interval Time on Brain Tissue Preservation
Blair, J. A., Wang, C., Hernandez, D., Siedlak, S., Rodgers, M. S., Achar, R. K., Fahmy, L. M., Torres, S., Petersen, R., Zhu, X.-W., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0151615 · Cited by 99 · see citing works
Gawryluk, J. W., Wang, J.-F., Andreazza, A. C., Shao, L., Yatham, L. N., & Young, L. T. (2011) · The International Journal of Neuropsychopharmacology · doi:10.1017/s1461145711000617 · Cited by 99 · see citing works
Impact of gender on upregulation of antioxidant defence mechanisms in Alzheimer?s disease brain
Schüssel, K., Leutner, S., Cairns, N. J., M�ller, W. E., & Eckert, A. (2004) · Journal of Neural Transmission · doi:10.1007/s00702-004-0156-5 · Cited by 95 · see citing works
Effect of Cerebral Amyloid Angiopathy on Brain Iron, Copper, and Zinc in Alzheimer's Disease
Schrag, M., Crofton, A. R., Zabel, M. K., Jiffry, A., Kirsch, D., Dickson, A., Mao, X. W., Vinters, H. V., Domaille, D. W., Chang, C. J., et al. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-101503 · Cited by 80 · see citing works
Self-citationLabak, M., Foniok, T., Kirk, D., Rushforth, D., Tomanek, B., Jasiński, A., & Grieb, P. (2010) · Acta neurochirurgica. Supplementum · doi:10.1007/978-3-211-98811-4_32 · Cited by 79 · see citing works
Ascorbic Acid and Rates of Cognitive Decline in Alzheimer's Disease
Bowman, G. L., Dodge, H. H., Frei, B. B., Calabrese, C., Oken, B., Kaye, J. A., & Quinn, J. F. (2009) · Journal of Alzheimer s Disease · doi:10.3233/jad-2009-0923 · Cited by 78 · see citing works
Prasanthi, J. R. P., Schrag, M., Dasari, B., Marwarha, G., Dickson, A., Kirsch, W. M., & Ghribi, O. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-111346 · Cited by 68 · see citing works
Self-citationPostmortem Brain Levels of Urate and Precursors in Parkinson's Disease and Related Disorders
McFarland, N. R., Burdett, T. C., Desjardins, C. A., Frosch, M. P., & Schwarzschild, M. A. (2013) · Neurodegenerative Diseases · doi:10.1159/000346370 · Cited by 58 · see citing works
Antioxidants in Alzheimer's disease-vitamin C delivery to a demanding brain
Quinn, J. F., Suh, J. H., Moore, M. M., Kaye, J. A., & Frei, B. B. (2003) · Journal of Alzheimer s Disease · doi:10.3233/jad-2003-5406 · Cited by 57 · see citing works
PtdIns5 P is an oxidative stress‐induced second messenger that regulates PKB activation
Jones, D. R., Foulger, R., Keune, W., et al. (2012) · The FASEB Journal · doi:10.1096/fj.12-218842 · Cited by 56 · see citing works
Bogdanović, N., Zilmer, M., Zilmer, K., Rehema, A., & Karelson, E. (2001) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000051282 · Cited by 53 · see citing works
Oxidative stress and APO E polymorphisms in Alzheimer's disease and in mild cognitive impairment
Chico, L., Simoncini, C., Gerfo, A. L., Rocchi, A., Petrozzi, L., Carlesi, C., Volpi, L., Tognoni, G., Siciliano, G., & Bonuccelli, U. (2013) · Free Radical Research · doi:10.3109/10715762.2013.804622 · Cited by 51 · see citing works
Harish, G., Venkateshappa, C., Mahadevan, A., Pruthi, N., Bharath, M. M. S., & Shankar, S. K. (2011) · Neurochemistry International · doi:10.1016/j.neuint.2011.08.024 · Cited by 42 · see citing works
Relationship between oxidative stress and apoE phenotype in Alzheimer's disease
Ihara, Y., Hayabara, T., Sasaki, K., Kawada, R., Nakashima, Y., & Kuroda, S. (2000) · Acta Neurologica Scandinavica · doi:10.1034/j.1600-0404.2000.102006346.x · Cited by 29 · see citing works
Harish, G., Venkateshappa, C., Mahadevan, A., et al. (2011) · Biopreservation and Biobanking · doi:10.1089/bio.2011.0033 · Cited by 17 · see citing works
Activation of metallothionein transcription by 4‐hydroxynonenal
Braithwaite, E. K., Mattie, M. D., & Freedman, J. H. (2010) · Journal of Biochemical and Molecular Toxicology · doi:10.1002/jbt.20342 · Cited by 15 · see citing works
Correction: Individual Case Analysis of Postmortem Interval Time on Brain Tissue Preservation
Blair, J. A., Wang, C., Hernandez, D., Siedlak, S., Rodgers, M. S., Achar, R., Fahmy, L. M., Torres, S., Petersen, R., Zhu, X.-W., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0157209 · Cited by 9 · see citing works
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Brandes, M. S., & Gray, N. E. (2020) · ASN Neuro · doi:10.1177/1759091419899782 · Cited by 297 · see citing works
Buccellato, F. R., D’Anca, M., Fenoglio, C., Scarpini, E., & Galimberti, D. (2021) · Antioxidants · doi:10.3390/antiox10091353 · Cited by 179 · see citing works
Stefanova, N. A., Ershov, N. I., & Kolosova, N. G. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/3984906 · Cited by 40 · see citing works
- Authors
- Zabel, M., Nackenoff, A., Kirsch, W. M., Harrison, F. E., Perry, G., & Schrag, M.
- Affiliations
- California Northstate University (US)
- Vanderbilt University (US)
- Loma Linda University (US)
- The University of Texas at San Antonio (US)
- Corresponding author
- Schrag, Matthew
- Venue
- Free Radical Biology and Medicine
- Publisher
- Elsevier BV
- Published
- 2018-02
- Volume
- 115
- Pages
- 351-360
- ISSN
- 0891-5849 (ISSN-L)
- PMC
- PMC6435270
- OpenAlex
- W2774814757
- Cited by
- 115
- References
- 49
- Citations by year
- 2026: 6 · 2025: 16 · 2024: 10 · 2023: 23 · 2022: 15 · 2021: 15 · 2020: 12 · 2019: 10 · 2018: 7 · 2013: 1
- FWCI
- 0.91
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Free Radical Biology and Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Vanderbilt University Medical Center's Faculty Research
- Topics
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, oxidative stress, lipid peroxidation, malondialdehyde, 4-hydroxynonenal, protein carbonylation, 8-oxoguanine, antioxidant enzymes, superoxide dismutase, glutathione peroxidase, catalase, glutathione, tocopherols, uric acid, vitamin C, regional brain differences, hippocampus, temporal lobe, occipital lobe, mild cognitive impairment, brain aging
- MeSH terms
- Alzheimer Disease, Antioxidants, Ascorbic Acid, Brain, Glutathione, Humans, Lipids, Nucleic Acids, Prognosis, Uric Acid, Biomarkers, Case-Control Studies, Oxidative Stress, Tocopherols, Lipid Metabolism
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