Elevated levels of pro‐apoptotic p53 and its oxidative modification by the lipid peroxidation product, HNE,in brain from subjects with amnestic mild cognitive impairment and Alzheimer's disease
Open accessAbstract
Oxidative stress has been implicated in the pathogenesis of Alzheimer's disease (AD). Both AD and arguably its earlier form, mild cognitive impairment (MCI), have elevated membrane oxidative damage in brain. The tumor suppressor and transcription factor p53 plays a pivotal function in neuronal apoptosis triggered by oxidative stress. Apoptosis contributes to neuronal death in many neurological disorders, including AD. In this study, we investigated p53 expression in a specific region of the cerebral cortex, namely the inferior parietal lobule (IPL), in MCI and AD brain, to test the hypothesis that alterations of this pro‐apoptotic protein may be involved in neuronal death in the progression of AD. By immunoprecipitation assay, we also investigated whether 4‐hydroxy‐2‐transnonenal (HNE), an aldehydic product of lipid peroxidation, was bound in excess to p53 in IPL from subjects with MCI and AD compared to control. Overall, the data provide evidence that p53 is involved in the neuronal death in both MCI and AD, suggesting that the observed alterations are early events in the progression of AD. In addition, HNE may be a novel non‐protein mediator of oxidative stress‐induced neuronal apoptosis.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
p53 is significantly modified by carbonylation, but not 3NT or HNE in MCI IPL.
“p53 is significantly modified by carbonylation, but not 3NT or HNE in MCI IPL [87,88].”
From Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease (2020) · cites this paper as [88]
The Results and discussion section (page unavailable) reports no significant difference in HNE bound to p53 in MCI inferior parietal lobule (IPL), supporting the HNE portion of the claim. It reports increased p53 levels in MCI IPL, but does not report significant p53 carbonylation or a 3NT result; increased protein level is not evidence of those modifications. (LLM, conf=0.90)
Experimental — accuracy not yet measuredp53 is significantly increased in MCI and AD IPL with p53 significantly modified by protein-bound HNE, 3-NT, and carbonyls in an AD brain.
“p53 is significantly increased in MCI and AD IPL with p53 significantly modified by protein-bound HNE, 3-NT, and carbonyls in an AD brain.”
From Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease (2020) · cites this paper as [88]
The Results and discussion report significantly increased p53 levels in MCI and AD inferior parietal lobule (IPL), and significantly increased HNE binding to p53 in AD IPL. Our copy does not report that p53 was significantly modified by 3-NT or carbonyls in AD brain; searches for those terms found no such result. No page number was provided in the indexed copy. (LLM, conf=0.90)
Experimental — accuracy not yet measuredIncreased p38MAPK activity is present in AD brains and lymphocytes and in the cortex of a mouse model of AD.
“Increased p38MAPK activity has been reported in AD brains and lymphocytes [205,206,207,208], as well as in the cortex of a mouse model of AD [209].”
From Ageing, Cellular Senescence and Neurodegenerative Disease (2018) · cites this paper as [205]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes
Esterbauer, H., Schaur, R. J., & Zollner, H. (1991) · Free Radical Biology and Medicine · doi:10.1016/0891-5849(91)90192-6 · Cited by 6,672 · see citing works
Crystal Structure of a p53 Tumor Suppressor-DNA Complex: Understanding Tumorigenic Mutations
Cho, Y., Gorina, S., Jeffrey, P. D., & Pavletich, N. P. (1994) · Science · doi:10.1126/science.8023157 · Cited by 2,559 · see citing works
Diagnosis of Alzheimer's Disease
Khachaturian, Z. S. (1985) · Archives of Neurology · doi:10.1001/archneur.1985.04060100083029 · Cited by 2,499 · see citing works
Oxidative stress hypothesis in Alzheimer’s disease
Markesbery, W. R. (1997) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(96)00629-6 · Cited by 2,383 · see citing works
p53: puzzle and paradigm.Preprint
Ko, L. J., & Prives, C. L. (1996) · Genes & Development · doi:10.1101/gad.10.9.1054 · Cited by 2,338 · see citing works
Oxygen radicals and human disease
CROSS, C. E., HALLIWELL, B., BORISH, E. T., PRYOR, W. A., AMES, B. N., SAUL, R. L., McCORD, J. M., & HARMAN, D. (1987) · Annals of Internal Medicine · doi:10.7326/0003-4819-107-4-526 · Cited by 1,856 · see citing works
Apoptosis in neurodegenerative disorders
Mattson, M. P. (2000) · Nature Reviews Molecular Cell Biology · doi:10.1038/35040009 · Cited by 1,605 · see citing works
4-Hydroxy-2-nonenal: a product and mediator of oxidative stress
Uchida, K. (2003) · Progress in Lipid Research · doi:10.1016/s0163-7827(03)00014-6 · Cited by 1,164 · see citing works
Butterfield, D. A., & Lauderback, C. M. (2002) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(02)00794-3 · Cited by 999 · see citing works
Self-citationHensley, K., Hall, N., Subramaniam, R., Cole, P., Harris, M., Aksenov, M., Aksenova, M., Gabbita, S. P., Wu, J. F., Carney, J. M., et al. (1995) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1995.65052146.x · Cited by 779 · see citing works
Self-citationEvidence that 4-Hydroxynonenal Mediates Oxidative Stress-Induced Neuronal Apoptosis
Kruman, I. I., Bruce‐Keller, A. J., Bredesen, D. E., Waeg, G., & Mattson, M. P. (1997) · Journal of Neuroscience · doi:10.1523/jneurosci.17-13-05089.1997 · Cited by 719 · see citing works
Markesbery, W. R., & Lovell, M. A. (1998) · Neurobiology of Aging · doi:10.1016/s0197-4580(98)00009-8 · Cited by 680 · see citing works
Butterfield, D. A., Reed, T., Newman, S. F., & Sultana, R. (2007) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2007.05.037 · Cited by 564 · see citing works
Self-citationp53 Induces Apoptosis by Caspase Activation through Mitochondrial Cytochrome c Release
Schüler, M., Bossy‐Wetzel, E., Goldstein, J. C., Fitzgerald, P., & Green, D. R. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.10.7337 · Cited by 558 · see citing works
Hensley, K., Maidt, M. L., Yu, Z., Sang, H., Markesbery, W. R., & Floyd, R. A. (1998) · Journal of Neuroscience · doi:10.1523/jneurosci.18-20-08126.1998 · Cited by 508 · see citing works
Lauderback, C. M., Hackett, J. M., Huang, F. F., Keller, J. N., Szweda, L. I., Markesbery, W. R., & Butterfield, D. A. (2001) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2001.00451.x · Cited by 464 · see citing works
Self-citationMontine, T. J., Neely, M. D., Quinn, J. F., Beal, M. F., Markesbery, W. R., Roberts, L. J., & Morrow, J. D. (2002) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(02)00807-9 · Cited by 449 · see citing works
Williams, T. I., Lynn, B. C., Markesbery, W. R., & Lovell, M. A. (2005) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2005.06.004 · Cited by 391 · see citing works
Butterfield, D. A., Poon, H. F., St. Clair, D., Keller, J. N., Pierce, W. M., Klein, J. B., & Markesbery, W. R. (2006) · Neurobiology of Disease · doi:10.1016/j.nbd.2005.11.002 · Cited by 377 · see citing works
Self-citationAdvances in Alzheimer's disease
Katzman, R., & Saitoh, T. (1991) · The FASEB Journal · doi:10.1096/fasebj.5.3.2001787 · Cited by 357 · see citing works
Rukhsana Sultana, A., Debra Boyd-kimball, A., Poon, H. F., Cai, J., Pierce, W. M. J., Klein, J. B., Merchant, M. L., Markesbery, W. R., & Butterfield, D. A. (2005) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2005.09.021 · Cited by 334 · see citing works
Self-citationCorrelates of p53- and Fas (CD95)-mediated apoptosis in Alzheimer's disease
de la Monte, S. M., Sohn, Y. K., & Wands, J. R. (1997) · Journal of the Neurological Sciences · doi:10.1016/s0022-510x(97)00131-7 · Cited by 307 · see citing works
Gottlieb, T. M., & Oren, M. (1998) · Seminars in Cancer Biology · doi:10.1006/scbi.1998.0098 · Cited by 301 · see citing works
Subramaniam, R., Roediger, F., Jordan, B., Mattson, M. P., Keller, J. N., Waeg, G., & Butterfield, D. A. (1997) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1997.69031161.x · Cited by 270 · see citing works
Self-citationSenile Dementia of the Alzheimer Type Without Neocortical Neurofibrillary Tangles
Terry, R. D., Hansen, L. A., DeTeresa, R. M., Davies, P., Tobias, H., & Katzman, R. (1987) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-198705000-00003 · Cited by 268 · see citing works
McGrath, L. T. (2001) · QJM · doi:10.1093/qjmed/94.9.485 · Cited by 253 · see citing works
Butterfield, D. A., Reed, T., Perluigi, M., De Marco, C., Coccia, R., Cini, C., & Sultana, R. (2006) · Neuroscience Letters · doi:10.1016/j.neulet.2005.12.017 · Cited by 246 · see citing works
Self-citationp53-Dependent Cell Death Signaling in Neurons
Morrison, R. S., Kinoshita, Y., Johnson, M. D., Guo, W., & Garden, G. A. (2003) · Neurochemical Research · doi:10.1023/a:1021687810103 · Cited by 186 · see citing works
Changes of p53 in the Brains of Patients with Alzheimer's Disease
Kitamura, Y., Shimohama, S., Kamoshima, W., Matsuoka, Y., Nomura, Y., & Taniguchi, T. (1997) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1997.6301 · Cited by 185 · see citing works
Mattson, M. P., Fu, W., Waeg, G., & Uchida, K. (1997) · NeuroReport · doi:10.1097/00001756-199707070-00036 · Cited by 176 · see citing works
Mild cognitive impairment clinical trials
Petersen, R. C. (2003) · Nature Reviews Drug Discovery · doi:10.1038/nrd1155 · Cited by 176 · see citing works
Selective increase in lipid peroxidation in the inferior temporal cortex in Alzheimer's disease
Palmer, A. M., & Burns, M. A. (1994) · Brain Research · doi:10.1016/0006-8993(94)91670-5 · Cited by 168 · see citing works
Redox signalling and transition metals in the control of the p53 pathway
Méplan, C., Richard, M., & Hainaut, P. L. (2000) · Biochemical Pharmacology · doi:10.1016/s0006-2952(99)00297-x · Cited by 163 · see citing works
Involvement of p53 in cell differentiation and development
Almog, N., & Rotter, V. (1997) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/s0304-419x(97)00012-7 · Cited by 160 · see citing works
Culmsee, C., Siewe, J., Junker, V., Retiounskaia, M., Schwarz, S., Camandola, S., El-Metainy, S., Behnke, H., Mattson, M. P., & Krieglstein, J. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-24-08586.2003 · Cited by 146 · see citing works
4-Hydroxynonenal Induces Apoptosis via Caspase-3 Activation and CytochromecRelease
Ji, C., Amarnath, V., Pietenpol, J. A., & Marnett, L. J. (2001) · Chemical Research in Toxicology · doi:10.1021/tx000186f · Cited by 143 · see citing works
da Costa, C. A., Paitel, E., Mattson, M. P., Amson, R. B., Telerman, A., Ancolio, K., & Checler, F. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.062059899 · Cited by 133 · see citing works
Uberti, D. L., Belloni, M., Grilli, M., Spano, P., & Memo, M. (1998) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.1998.00042.x · Cited by 104 · see citing works
Self-citationBarcikowska, M., Wisniewski, H. M., Bancher, C., & Grundke, I. (1989) · Acta Neuropathologica · doi:10.1007/bf00687751 · Cited by 103 · see citing works
4-Hydroxynonenal oxidatively modifies histones: implications for Alzheimer's disease
Drake, J., Petroze, R. T., Castegna, A., Ding, Q., Keller, J. N., Markesbery, W. R., Lovell, M. A., & Butterfield, D. A. (2004) · Neuroscience Letters · doi:10.1016/j.neulet.2003.11.047 · Cited by 77 · see citing works
Self-citationGilman, C. P., Chan, S. L., Guo, Z., Zhu, X., Greig, N. H., & Mattson, M. P. (2003) · NeuroMolecular Medicine · doi:10.1385/nmm:3:3:159 · Cited by 77 · see citing works
Li, J., Sharma, R., Patrick, B., et al. (2006) · Biochemistry · doi:10.1021/bi060780+ · Cited by 54 · see citing works
p53 DNA binding can be modulated by factors that alter the conformational equilibrium
McLure, K. G., & Lee, P. W. K. (1999) · The EMBO Journal · doi:10.1093/emboj/18.3.763 · Cited by 54 · see citing works
Uchida, K., Osawa, T., Hiai, H., et al. (1995) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1995.2078 · Cited by 38 · see citing works
Flagged first, then by citations
Research works printed but not linked: 4
- [13]Sansome C Zaika A Marchenko ND Moll UM Hypoxia death stimulus induces translocation of p53 protein to mitochondria. Detection by immunofluorescence on whole cells FEBS Lett 2001 488 110 5 11163756
- [14]Marchenko ND Zaika A Moll UM Death signalinduced localization of p53 protein to mitochondria. A potential role in apoptotic signaling J Biol Chem 2000 275 16202 12 10821866
- [34]McKhann G Drachman D Folstein M Katzman R Price D Stadlan EM Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease Neurology 1984 34 939 44 6610841
- [49]Pratico D Clark CM Liun F Rokach J Lee VY Trojanowski JQ Increase of brain oxidative stress in mild cognitive impairment: a possible predictor of Alzheimer disease Arch Neurol 2002 59 972 6 12056933
Cited by
Sorted by citations
Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease
Stockwell, B. R., Friedmann Angeli, J. P., Bayir, H., Bush, A. I., Conrad, M., Dixon, S. J., Fulda, S., Gascón, S., Hatzios, S. K., Kagan, V. E., et al. (2017) · Cell · doi:10.1016/j.cell.2017.09.021 · Cited by 7,695 · see citing works
Ageing, Cellular Senescence and Neurodegenerative Disease
Kritsilis, M., V. Rizou, S., Koutsoudaki, P. N., Evangelou, K., Gorgoulis, V. G., & Papadopoulos, D. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19102937 · Cited by 448 · see citing works
Butterfield, D. A., & Boyd-Kimball, D. (2018) · Journal of Alzheimer’s Disease · doi:10.3233/jad-170543 · Cited by 403 · see citing works
Self-citationOxidative stress and β-amyloid protein in Alzheimer’s disease
Cai, Z., Zhao, B., & Ratka, A. (2011) · NeuroMolecular Medicine · doi:10.1007/s12017-011-8155-9 · Cited by 279 · see citing works
Lanni, C., Masi, M., Racchi, M., & Govoni, S. (2021) · Molecular Psychiatry · doi:10.1038/s41380-020-0760-2 · Cited by 130 · see citing works
Butterfield, D. A. (2014) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2014.06.006 · Cited by 126 · see citing works
Self-citationMitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease
Butterfield, D. A., & Boyd-Kimball, D. (2020) · Antioxidants · doi:10.3390/antiox9090818 · Cited by 85 · see citing works
“MnSOD is oxidatively modified by HNE in early AD IPL, resulting in a significant decrease in enzyme activity [55] and is also oxidatively modified by HNE in late AD IPL [54].”
BackgroundInfluentialSelf-citationCenini, G., Sultana, R., Memo, M., & Butterfield, D. A. (2008) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2008.03.015 · Cited by 79 · see citing works
Self-citationLiu, Y., Chen, Z., Li, B., Yao, H., Zarka, M., Welch, J., Sachdev, P., Bridge, W., & Braidy, N. (2021) · Neurochemistry International · doi:10.1016/j.neuint.2020.104931 · Cited by 69 · see citing works
Nalapareddy, K., Jiang, H., Gutierrez, L. M. G., & Rudolph, K. L. (2008) · Experimental Gerontology · doi:10.1016/j.exger.2008.09.002 · Cited by 50 · see citing works
Silva, A. R. T., Grinberg, L. T., Farfel, J. M., Diniz, B. S., Lima, L. A., Silva, P. J. S., Ferretti, R. E. L., Rocha, R. M., Filho, W. J., Carraro, D. M., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0048751 · Cited by 40 · see citing works
Tramutola, A., Pupo, G., Di Domenico, F., Barone, E., Arena, A., Lanzillotta, C., Broekaart, D., Blarzino, C., Head, E., Butterfield, D. A., et al. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-151105 · Cited by 40 · see citing works
Self-citationFiorini, A., Sultana, R., Barone, E., Cenini, G., Perluigi, M., Mancuso, C., Cai, J., Klein, J. B., St. Clair, D., & Butterfield, D. A. (2012) · PLoS ONE · doi:10.1371/journal.pone.0049846 · Cited by 16 · see citing works
Self-citation
- Authors
- Cenini, G., Sultana, R., Memo, M., & Butterfield, D. A.
- Affiliations
- University of Kentucky (US)
- University of Brescia (IT)
- Corresponding author
- Butterfield, D. Allan
- Venue
- Journal of Cellular and Molecular Medicine
- Publisher
- Wiley
- Published
- 2008-05-21
- Volume
- 12
- Issue
- 3
- Pages
- 987-994
- ISSN
- 1582-1838 (ISSN-L)
- 1582-4934
- PMC
- PMC4401131
- OpenAlex
- W2155589424
- Cited by
- 117
- References
- 45
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 3 · 2023: 11 · 2022: 2 · 2021: 9 · 2020: 12 · 2019: 8 · 2018: 4 · 2017: 5 · 2016: 5 · 2015: 4 · 2014: 7 · 2013: 4 · 2012: 7
- FWCI
- 6.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Cellular and Molecular Medicine (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UKnowledge (University of Kentucky) (submittedVersion)
- Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion)
- Funders
- National Institutes of Health (AG-10836, AG-05119)
- National Institute on Aging (P01AG010836, P01AG005119, AG 10836, AG0 5119)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Keywords
- p53, lipid peroxidation, oxidative stress, neuronal apoptosis, amnestic mild cognitive impairment, Alzheimer's disease, inferior parietal lobule, cerebral cortex, neuronal cell death
- MeSH terms
- Aged, 80 and over, Aldehydes, Alzheimer Disease, Amnesia, Brain, Cognition Disorders, Female, Humans, Longitudinal Studies, Male, Oxidation-Reduction, Parietal Lobe, Lipid Peroxidation, Case-Control Studies, Tumor Suppressor Protein p53, Apoptosis, Oxidative Stress, Disease Progression
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
