NAD(P)H:quinone oxidoreductase activity is increased in hippocampal pyramidal neurons of patients with alzheimer’s disease
Abstract
NAD(P)H:quinone oxidoreductase (QR) catalyzes the two-electron reduction of quinones, preventing their participation in redox cycling and subsequent generation of reactive oxygen species. Pretreatment of neuroblastoma cells with compounds, such as tert-butylhydroquinone and dimethyl fumarate, that increase QR expression protect cells from oxidative stress-induced cell death by glutamate, H(2)O(2,) and dopamine. The potential neuroprotective role of QR as well as the evidence for oxidative stress-induced neuronal cell death in Alzheimer's disease (AD) led us to examine the expression pattern of QR from AD and control patients. Histochemical staining of hippocampal sections from AD patients revealed QR activity in pyramidal neurons. The presence of QR protein in these neurons also was confirmed by immunoreactivity. In control patients, hippocampal pyramidal neurons were negative for both QR enzymatic activity and QR immunoreactivity. In addition, the QR positive neurons of AD patients were selectively located in areas where neuronal populations exhibited tau immunostaining. Our data demonstrate that QR is up-regulated in hippocampal pyramidal neurons of AD patients. We hypothesize that this is part of a neuroprotective system up-regulated in response to the AD process. Understanding this system may lead to further insights into the pathogenesis and potential new avenues of treatment for AD.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Numerous other studies demonstrate both an increase and decrease in ARE gene expression in AD brain tissue, with an initial heightened antioxidant response due to oxidative stress followed by eventual exhaustion with decrease of ARE pathway signaling.
“Numerous other studies demonstrate both an increase and decrease in ARE gene expression in AD brain tissue, citing an initial heightened antioxidant response due to oxidative stress [22,86,87], followed by its eventual exhaustion with the decrease of ARE pathway signaling [88].”
From Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice (2019) · cites this paper as [87]
Cites
McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D., & Stadlan, E. M. (1984) · Neurology · doi:10.1212/wnl.34.7.939 · Cited by 27,915 · see citing works
Neuropathological stageing of Alzheimer-related changes.
Braak, H., & Braak, E. (1991) · Acta Neuropathologica · doi:10.1007/bf00308809 · Cited by 16,123 · see citing works
Lambert, M. P., Barlow, A. K., Chromy, B. A., Edwards, C., Freed, R., Liosatos, M., Morgan, T. E., Rozovsky, I., Trommer, B., Viola, K. L., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.11.6448 · Cited by 3,506 · see citing works
Rushmore, T. H., Morton, M. R., & Pickett, C. B. (1991) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)99004-6 · Cited by 1,464 · see citing works
Neurodegeneration induced by beta-amyloid peptides in vitro: the role of peptide assembly state
Pike, C., Burdick, D., Walencewicz, A., Glabe, C., & Cotman, C. (1993) · The Journal of Neuroscience · doi:10.1523/jneurosci.13-04-01676.1993 · Cited by 1,417 · see citing works
The Clinical Diagnosis of Alzheimer's Disease
Wade, J. P. H., Mirsen, T. R., Hachinski, V. C., Fisman, M., Lau, C. S., & Merskey, H. (1987) · Archives of Neurology · doi:10.1001/archneur.1987.00520130016010 · Cited by 1,416 · see citing works
Murphy, T. H., Miyamoto, M., Sastre, A., Schnaar, R. L., & COYLE, J. T. (1989) · Neuron · doi:10.1016/0896-6273(89)90043-3 · Cited by 1,033 · see citing works
Functional antioxidant responsive elements
Wasserman, W. W., & Fahl, W. E. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.10.5361 · Cited by 705 · see citing works
Lind, C., Hochstein, P., & Ernster, L. (1982) · Archives of Biochemistry and Biophysics · doi:10.1016/0003-9861(82)90202-8 · Cited by 530 · see citing works
Rushmore, T. H., & Pickett, C. B. (1990) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)77351-1 · Cited by 522 · see citing works
Dt diaphorase I. Purification from the soluble fraction of rat-liver cytoplasm, and properties
Ernster, L., Danielson, L., & Ljunggren, M. (1962) · Biochimica et Biophysica Acta · doi:10.1016/0006-3002(62)90997-6 · Cited by 483 · see citing works
Friling, R. S., Bensimon, A., Tichauer, Y., & Daniel, V. (1990) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.87.16.6258 · Cited by 475 · see citing works
Mulcahy, R., Wartman, M. A., Bailey, H. H., & Gipp, J. J. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.11.7445 · Cited by 455 · see citing works
Chemical and molecular regulation of enzymes that detoxify carcinogens.
Prestera, T., Holtzclaw, W. D., Zhang, Y., & Talalay, P. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.7.2965 · Cited by 416 · see citing works
Mutagenicity of quinones: pathways of metabolic activation and detoxification.
Chesis, P. L., Levin, D. E., Smith, M. T., Ernster, L., & Ames, B. N. (1984) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.81.6.1696 · Cited by 388 · see citing works
p38 Kinase Is Activated in the Alzheimer's Disease Brain
Hensley, K., Floyd, R. A., Zheng, N., Nael, R., Robinson, K. A., Nguyen, X., Pye, Q. N., Stewart, C. A., Geddes, J., Markesbery, W. R., et al. (1999) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1999.0722053.x · Cited by 373 · see citing works
Characterization of a polymorphism in NAD(P)H: quinone oxidoreductase (DT-diaphorase)
Traver, R. D., Siegel, D. M., Beall, H. D., et al. (1997) · British Journal of Cancer · doi:10.1038/bjc.1997.11 · Cited by 307 · see citing works
Antioxidant and prooxidant functions of DT-diaphorase in quinone metabolism
Cadenas, E. (1995) · Biochemical Pharmacology · doi:10.1016/s0006-2952(94)00333-5 · Cited by 273 · see citing works
Dalton, T. P., Palmiter, R. D., & Andrews, G. K. (1994) · Nucleic Acids Research · doi:10.1093/nar/22.23.5016 · Cited by 265 · see citing works
β-Amyloid and the Pathogenesis of Alzheimer's Disease
Flier, J. S., Underhill, L. H., Yankner, B. A., & Mesulam, M. M. (1991) · New England Journal of Medicine · doi:10.1056/nejm199112263252605 · Cited by 207 · see citing works
Immunohistochemical detection of NAD(P)H:quinone oxidoreductase in human lung and lung tumors.
Siegel, D. M., Franklin, W. A., & Ross, D. (1998) · PubMed · Cited by 165 · see citing works
Rifampicin Prevents the Aggregation and Neurotoxicity of Amyloid β Protein in Vitro
Tomiyama, T., Asano, S., Suwa, Y., Morita, T., Kataoka, K., Mori, H., & Endo, N. (1994) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1994.2428 · Cited by 158 · see citing works
Duffy, S., So, A. P., & Murphy, T. H. (1998) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1998.71010069.x · Cited by 145 · see citing works
Soluble Diaphorase in Animal Tissues.
Ernster, L., Navazio, F. M., Löw, H., Siekevitz, P., Ernster, L., & Diczfalusy, E. R. (1958) · Acta chemica Scandinavica/Acta chemica Scandinavica. B, Organic chemistry and biochemistry/Acta chemica Scandinavica. A, Physical and inorganic chemistry/Acta chemica Scandinavica. Series B. Organic chemistry and biochemistry/Acta chemica Scandinavica. Series A, Physical and inorganic chemistry · doi:10.3891/acta.chem.scand.12-0595 · Cited by 140 · see citing works
The structure of the rat glutathione S-transferase P gene and related pseudogenes.
Okuda, A., Sakai, M., & Muramatsu, M. (1987) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)61435-8 · Cited by 131 · see citing works
Quinone reductase (NQO1), a sensitive redox indicator, is increased in Alzheimer’s disease
Raina, A. K., Templeton, D. J., deak, J. C., Perry, G., & Smith, M. A. (1999) · Redox Report · doi:10.1179/135100099101534701 · Cited by 120 · see citing works
Lind, C., Vadi, H. V., & Ernster, L. (1978) · Archives of Biochemistry and Biophysics · doi:10.1016/0003-9861(78)90256-4 · Cited by 117 · see citing works
Hensley, K., BUTTERFIELDLD, D. A., Hall, N. C., COLE, P., Subramaniam, R., Mark, R. J., Mattson, M. P., Markesbery, W. R., Harris‐White, M. E., Aksenov, M. Y., et al. (1996) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1996.tb39057.x · Cited by 117 · see citing works
Yu, R., Tan, T., & Kong, A.-N. T. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.46.28962 · Cited by 116 · see citing works
Landi, L., Fiorentini, D., Galli, M. C., Segura‐Aguilar, J., & Beyer, R. E. (1997) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(96)00294-8 · Cited by 104 · see citing works
Ng, D., Kokot, N., Hiura, T. S., Faris, M., Saxon, A., & Nel, A. E. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.161.2.942 · Cited by 97 · see citing works
Signal transduction abnormalities in Alzheimer's disease: evidence of a pathogenic stimuli.
Mcshea, A., Zelasko, D. A., Gerst, J. L., & Smith, M. A. (1999) · Brain Research · doi:10.1016/s0006-8993(98)01135-4 · Cited by 95 · see citing works
Activation of Antioxidant/Electrophile-Responsive Elements in IMR-32 Human Neuroblastoma Cells
Moehlenkamp, J. D., & Johnson, J. A. (1999) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.1998.1046 · Cited by 80 · see citing works
Self-citationEnhanced NAD(P)H:Quinone Reductase Activity Prevents Glutamate Toxicity Produced by Oxidative Stress
Murphy, T. H., Long, M. J., & Coyle, J. T. (1991) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1991.tb02019.x · Cited by 79 · see citing works
Cloning and characterization of the murine manganous superoxide dismutase-encoding gene
Jones, P. L., Kucera, G., Gordon, H., & Boss, J. M. (1995) · Gene · doi:10.1016/0378-1119(94)00666-g · Cited by 74 · see citing works
Goodman, Y., & Mattson, M. P. (1994) · Brain Research · doi:10.1016/0006-8993(94)90223-2 · Cited by 59 · see citing works
Molecular Mechanisms of Dementia
Wasco, W., Tanzi, R. E., & Hulette, C. (1997) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-199705000-00013 · Cited by 57 · see citing works
DT-diaphorase-catalyzed two electron reduction of quinone epoxides
Brunmark, A. B., Cadenas, E., Lind, C., et al. (1987) · Free Radical Biology and Medicine · doi:10.1016/0891-5849(87)90003-7 · Cited by 54 · see citing works
Pulford, D. J., & Hayes, J. D. (1996) · Biochemical Journal · doi:10.1042/bj3180075 · Cited by 40 · see citing works
Azo dyes prevent hydrocarbon-induced leukemia in the rat.
Huggins, C., Ueda, N., & Russo, A. (1978) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.75.9.4524 · Cited by 38 · see citing works
Histochemical Detection of Quinone Reductase Activity In Situ Using LY 83583 Reduction and Oxidation
Murphy, T. H., So, A. P., & Vincent, S. R. (1998) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1998.70052156.x · Cited by 29 · see citing works
Molecular Mechanisms of Dementia
Rubinsztein, D. C. (1997) · Journal of Medical Genetics · doi:10.1136/jmg.34.9.791-a · Cited by 29 · see citing works
5'-Flanking sequence of mouse glutathione S-transferase Ya gene
Daniel, V., Tichauer, Y., & Sharon, R. (1988) · Nucleic Acids Research · doi:10.1093/nar/16.1.351 · Cited by 23 · see citing works
β-amyloid-Derived Free Radical Oxidation: A Fundamental Process in Alzheimers Disease
Butterfield, D. A., Hensley, K., Hall, N. C., et al. (2003) · Humana Press eBooks · doi:10.1385/0-89603-371-6:145 · Cited by 20 · see citing works
β-amyloid-Derived Free Radical Oxidation
Butterfield, D. A., Hensley, K., Hall, N. C., Ramachandran, S., Howard, B. J., Cole, P. S., Yatin, S. M., LaFontaine, M., Harris‐White, M. E., Aksenova, M. V., et al. (1997) · Humana Press eBooks · doi:10.1007/978-1-59259-471-9_9 · Cited by 4 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Multi-target-Directed Ligands To Combat Neurodegenerative Diseases
Cavalli, A., Bolognesi, M. L., Minarini, A., Rosini, M., Tumiatti, V., Recanatini, M., & Melchiorre, C. (2008) · Journal of Medicinal Chemistry · doi:10.1021/jm7009364 · Cited by 1,152 · see citing works
Expression of Nrf2 in Neurodegenerative Diseases
Ramsey, C. P., Glass, C. A., Montgomery, M. B., Lindl, K. A., Ritson, G. P., Chia, L. A., Hamilton, R. L., Chu, C. T., & Jordan-Sciutto, K. L. (2007) · Journal of Neuropathology and Experimental Neurology · doi:10.1097/nen.0b013e31802d6da9 · Cited by 760 · see citing works
Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis
Tian, R., Abarientos, A., Hong, J., Hashemi, S. H., Yan, R., Dräger, N., Leng, K., Nalls, M. A., Singleton, A. B., Xu, K., et al. (2021) · Nature Neuroscience · doi:10.1038/s41593-021-00862-0 · Cited by 414 · see citing works
Oxidative damage and the Nrf2-ARE pathway in neurodegenerative diseases
Gan, L., & Johnson, J. A. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.12.011 · Cited by 288 · see citing works
Self-citationRegional NAD(P)H:quinone oxidoreductase activity in Alzheimer’s disease
SantaCruz, K. S., Yazlovitskaya, E., Collins, J., Johnson, J., & DeCarli, C. (2004) · Neurobiology of Aging · doi:10.1016/s0197-4580(03)00117-9 · Cited by 116 · see citing works
Self-citationCentella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice
Matthews, D. G., Caruso, M., Murchison, C. F., Zhu, J. Y., Wright, K. M., Harris, C. J., Gray, N. E., Quinn, J. F., & Soumyanath, A. (2019) · Antioxidants · doi:10.3390/antiox8120630 · Cited by 86 · see citing works
“Numerous other studies demonstrate both an increase and decrease in ARE gene expression in AD brain tissue, citing an initial heightened antioxidant response due to oxidative stress [22,86,87], followed by its eventual exhaustion with the decrease of ARE pathway signaling [88].”
Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis
Tian, R., Abarientos, A., Hong, J., Hashemi, S. H., Yan, R., Dräger, N., Leng, K., Nalls, M. A., Singleton, A. B., Xu, K., et al. (2020) · doi:10.1101/2020.06.27.175679 · Cited by 414 · see citing works
Cuadrado, A., Cazalla, E., Bach, A., Bathish, B., Naidu, S. D., DeNicola, G. M., Dinkova-Kostova, A. T., Fernández-Ginés, R., Grochot-Przeczek, A., Hayes, J. D., et al. (2025) · Redox Biology · doi:10.1016/j.redox.2025.103569 · Cited by 28 · see citing works
- Authors
- Wang, Y., Santa–Cruz, K., DeCarli, C., & Johnson, J. A.
- Affiliations
- University of Kansas Medical Center (US)
- Corresponding author
- Johnson, Jeffrey A
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2000-07
- Volume
- 21
- Issue
- 4
- Pages
- 525-531
- ISSN
- 0197-4580 (ISSN-L)
- OpenAlex
- W2038899025
- Cited by
- 87
- References
- 45
- Citations by year
- 2025: 5 · 2024: 5 · 2023: 3 · 2022: 5 · 2021: 7 · 2020: 5 · 2019: 6 · 2018: 2 · 2017: 4 · 2016: 5 · 2015: 5 · 2014: 3 · 2013: 3 · 2012: 2
- FWCI
- 1.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5p30ag010182-05)
- National Institute on Aging (AG 10182)
- National Institute of Environmental Health Sciences (ES08089)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Coenzyme Q10 studies and effects
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
- Keywords
- NAD(P)H:quinone oxidoreductase, Alzheimer's disease, hippocampal pyramidal neurons, oxidative stress, neuroprotection, quinone reduction, reactive oxygen species, tau protein, glutathione reductase, neurodegeneration
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Hippocampus, Humans, Blotting, Western, NAD(P)H Dehydrogenase (Quinone), tau Proteins, Cell Death, Pyramidal Cells, Oxidative Stress
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review