Neurofilaments are the major neuronal target of hydroxynonenal-mediated protein cross-links
Open accessAbstract
Lipid peroxidation generates reactive aldehydes, most notably hydroxynonenal (HNE), which covalently binds amino acid residue side chains leading to protein inactivation and insolubility. Specific adducts of lipid peroxidation have been demonstrated to be intimately associated with pathological lesions of Alzheimer's disease (AD), suggesting that oxidative stress is a major component in the disease. Here, we examined the HNE-cross-linking modifications by using an antibody specific for a lysine-lysine cross-link. Since in a prior study we noted no immunolabeling of neuritic plaques or neurofibrillary tangles but instead found strong labeling of axons, we focused this study on axons. Axonal labeling was examined in mouse sciatic nerve, and immunoblotting showed the cross-link was restricted to neurofilament heavy and medium subunits, which while altering migration, did not indicate larger NF aggregates, indicative of intermolecular cross-links. Examination of mice at various ages showed the extent of modification remaining relatively constant through the life span. These findings demonstrate lipid-cross-linking peroxidation primarily involves lysine-rich neurofilaments and is restricted to intramolecular cross-links.
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Increased levels of 4-hydroxy-2-trans-nonenal are observed in Alzheimer's disease and mild cognitive impairment brains.
“Increased levels of HNE are observed in AD and MCI brains [24,38].”
From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [38]
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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
Sayre, L., Zelasko, D. A., Harris, P. L. R., Perry, G., Salomon, R. G., & Smith, M. A. (1997) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1997.68052092.x · Cited by 1,032 · see citing works
Protein-bound acrolein: Potential markers for oxidative stress
Uchida, K., Kanematsu, M., Sakai, K., Matsuda, T., Hattori, N., Mizuno, Y., Suzuki, D., Miyata, T., Noguchi, N., Niki, E., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.9.4882 · Cited by 632 · see citing works
Glycated tau protein in Alzheimer disease: a mechanism for induction of oxidant stress.
Yan, S. D., Chen, X., Schmidt, A. M., Brett, J., Godman, G., Zou, Y. S., Scott, C. W., Caputo, C., Frappier, T., & Smith, M. A. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.16.7787 · Cited by 565 · see citing works
Friguet, B., Stadtman, E. R., & Szweda, L. I. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)31853-7 · Cited by 311 · see citing works
Szweda, L. I., Uchida, K., Tsai, L., & Stadtman, E. R. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)53699-1 · Cited by 285 · see citing works
Castellani, R. J., Harris, P. L. R., Sayre, L. M., Fujii, J., Taniguchi, N., Vitek, M. P., Founds, H., Atwood, C., Perry, G. L., & Smith, M. A. (2001) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(01)00570-6 · Cited by 198 · see citing works
Autophagocytosis of Mitochondria Is Prominent in Alzheimer Disease
Moreira, P. I., Siedlak, S. L., Wang, X., Santos, M. S., Oliveira, C. R., Tabaton, M., Nunomura, A., Szweda, L. I., Aliev, G. M., Smith, M. A., et al. (2007) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/01.jnen.0000240476.73532.b0 · Cited by 145 · see citing works
Nunomura, A., Tamaoki, T., Motohashi, N., Nakamura, M., McKeel, D. W., Tabaton, M., Lee, H., Smith, M. A., Perry, G. L., & Zhu, X. (2012) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e318248e614 · Cited by 131 · see citing works
Wataya, T., Nunomura, A., Smith, M. A., Siedlak, S. L., Harris, P. L. R., Shimohama, S., Szweda, L. I., Kaminski, M. A., Ávila, J., Price, D. L., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m110913200 · Cited by 128 · see citing works
Tsai, L., Szweda, P. A., Vinogradova, O., & Szweda, L. I. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.14.7975 · Cited by 115 · see citing works
Rukhsana Sultana, A., & Butterfield, D. A. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-129018 · Cited by 83 · see citing works
Zhu, X., Castellani, R. J., Moreira, P. I., Aliev, G. M., Shenk, J. C., Siedlak, S. L., Harris, P. L. R., Fujioka, H., Sayre, L. M., Szweda, P. A., et al. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.11.004 · Cited by 46 · see citing works
Age-related increase in liver retinyl palmitate. Relationship to lipofuscin.
Szweda, L. I. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)37026-6 · Cited by 19 · see citing works
(2007) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/01.jnen.0000263876.99435.cb · Cited by 4 · see citing works
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Cell death and diseases related to oxidative stress: 4-hydroxynonenal (HNE) in the balance
Dalleau, S., Baradat, M., Guéraud, F., & Huc, L. (2013) · Cell Death & Differentiation · doi:10.1038/cdd.2013.138 · Cited by 580 · see citing works
4-Hydroxy-nonenal—A Bioactive Lipid Peroxidation Product
Schaur, R. J., Siems, W., Bresgen, N., & Eckl, P. (2015) · Biomolecules · doi:10.3390/biom5042247 · Cited by 231 · see citing works
Schwarzer, E., Arese, P., & Skorokhod, O. A. (2015) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2015/638416 · Cited by 202 · 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
A ferroptosis–based panel of prognostic biomarkers for Amyotrophic Lateral Sclerosis
Devos, D., Moreau, C., Kyheng, M., Garçon, G., Rolland, A., Blasco, H., Gelé, P., Lenglet, T., Veyrat‐Durebex, C., Corcia, P., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-39739-5 · Cited by 138 · see citing works
Protein lipoxidation: Detection strategies and challenges
Aldini, G., Domingues, M. R., Spickett, C. M., Domingues, P. M., Altomare, A., Sánchez-Gómez, F. J., Oeste, C. L., & Pérez‐Sala, D. (2015) · Redox Biology · doi:10.1016/j.redox.2015.05.003 · Cited by 81 · see citing works
Jové, M., Pradas, I., Domínguez-González, M., Ferrer, I., & Pamplona, R. (2018) · Redox Biology · doi:10.1016/j.redox.2018.101082 · Cited by 79 · see citing works
Hormetic and regulatory effects of lipid peroxidation mediators in pancreatic beta cells
Maulucci, G., Daniel, B., Cohen, O., Avrahami, Y., & Sasson, S. (2016) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2016.03.001 · Cited by 63 · see citing works
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Redox lipidomics to better understand brain aging and function
Pamplona, R., Borrás, C., Jové, M., Pradas, I., Ferrer, I., & Viña, J. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.03.016 · Cited by 38 · see citing works
Domínguez, M., de Oliveira, E., Odena, M. A., Portero‐Otín, M., Pamplona, R., & Ferrer, I. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.02.034 · Cited by 31 · see citing works
Extracellular Vesicles and Cancer Therapy: Insights into the Role of Oxidative Stress
Ho, J., Chaiswing, L., & Clair, D. K. S. (2022) · Antioxidants · doi:10.3390/antiox11061194 · Cited by 26 · see citing works
Jaganjac, M., Marković, A. S., Deiana, N., & Žarković, N. (2025) · Frontiers in Bioscience-Landmark · doi:10.31083/fbl37139 · Cited by 10 · see citing works
Proteomics and lipidomics in the human brain
Ferrer, I. (2018) · Handbook of clinical neurology · doi:10.1016/b978-0-444-63639-3.00020-7 · Cited by 10 · see citing works
Mass Spectrometry‐Based Platforms for Protein Lipoxidation Profiling
Tang, Z., Wang, T., & Liu, C. (2024) · Chemistry - A European Journal · doi:10.1002/chem.202402062 · Cited by 2 · see citing works
Crosstalk between cysteine and lysine modifications: Integrating redox and metabolic regulation
Mitchem, E. C., Roede, J. R., & Fritz, K. S. (2026) · Redox Biology · doi:10.1016/j.redox.2026.104357 · Cited by 1 · see citing works
- Authors
- Perry, E. A., Castellani, R. J., Moreira, P. I., Nunomura, A., Lui, Q., Harris, P. L. R., Sayre, L. M., Szweda, P. A., Szweda, L. I., Zhu, X., Smith, M. A., & Perry, G.
- Affiliations
- The University of Texas at San Antonio (US)
- University of Maryland, Baltimore (US)
- Centro de Neurociências e Biologia Celular (PT)
- University of Yamanashi (JP)
- Case Western Reserve University (US)
- Oklahoma Medical Research Foundation (US)
- Corresponding author
- Perry, G.
- ORCID
- Venue
- Free Radical Research
- Publisher
- Informa UK Limited
- Published
- 2013-05-10
- Volume
- 47
- Issue
- 6-7
- Pages
- 507-510
- ISSN
- 1029-2470 (ISSN-L)
- 1071-5762
- PMC
- PMC4097390
- OpenAlex
- W2023611061
- Cited by
- 16
- References
- 15
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2022: 1 · 2021: 2 · 2019: 2 · 2018: 2 · 2016: 2 · 2015: 3 · 2013: 1
- FWCI
- 1.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Free Radical Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute on Minority Health and Health Disparities (G12MD007591)
- Topics
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- 4-hydroxynonenal, neurofilaments, lipid peroxidation, protein cross-linking, oxidative stress, Alzheimer's disease, axons, intramolecular cross-links, lysine-rich proteins, aging
- MeSH terms
- Aldehydes, Animals, Antibodies, Fluorescence, Lysine, Mice, Inbred Strains, Sciatic Nerve, Neurofilament Proteins, Mice
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