Methemoglobinemia—A biomarker and a link to ferric iron accumulation in Alzheimer’s disease
Lucijan Mohorovic, Anna M. Lavezzi, Sanja Stifter, George Perry, Djulija Malatestinic, Vladimir Micovic, Eris Materljan, Herman Haller, Oleg Petrovic
“Lino Rossi” Research Center, Department of Biomedical, Sur-gical, and Dental Science, University of Milan, Milan, Italy.
Department of Biology, University of Texas at San Antonio, San Antonio, USA.
Department of Environmental Medicine, University of Rijeka School of Medicine, Rijeka, Croatia.
Department of Family Medicine, University of Rijeka School of Medicine, Rijeka, Croatia.
Department of Gynecology and Obstetrics, University of Rijeka School of Medicine, Rijeka, Croatia.
Department of Pathology, University of Rijeka School of Medi-cine, Rijeka, Croatia.
Department of Social Medicine and Epidemiology, University of Rijeka School of Medicine, Rijeka, Croatia.
DOI: 10.4236/abb.2014.51003   PDF   HTML   XML   4,132 Downloads   6,155 Views   Citations


Understanding the mechanism of oxidative stress is likely to yield new insights regarding the pathogenesis of Alzheimer’s disease (AD). Our earlier work focused on the difference between hemoglobin and methemoglobin degradation, respectively leading to ferrous (Fe2+) iron, or ferric (Fe3+) iron. Methemoglobin has the role of carrier, the donor of cytotoxic and redox-active ferric (Fe3+) iron, which can directly accumulate and increase the rate of capillary endothelial cell apoptosis, and may cross into the brain parenchyma, to the astrocytes, glia, neurons, and other neuronal cells (neurovascular unit). This supposition helps us to understand the transport and neuronal accumulation process of ferric iron, and determine how iron is transported and accumulated intracellularly, identifiable as “Brain rust”. Earlier research found that the incidences of neonatal jaundice (p = 0.034), heart murmur (p = 0.011) and disorders such as dyslalia and learning/memory impairments (p = 0.002) were significantly higher in those children born from mothers with methemoglobinemia. Our hypothesis suggests that prenatal iron abnormalities could lead to greater neuronal death, the disease ageing process, and neurodegenerative disorders such as AD and other neurodegenerative diseases.

Share and Cite:

Mohorovic, L. , Lavezzi, A. , Stifter, S. , Perry, G. , Malatestinic, D. , Micovic, V. , Materljan, E. , Haller, H. and Petrovic, O. (2014) Methemoglobinemia—A biomarker and a link to ferric iron accumulation in Alzheimer’s disease. Advances in Bioscience and Biotechnology, 5, 12-18. doi: 10.4236/abb.2014.51003.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Mohorovic, L., Materljan, E., Micovic, V., Malatestinic, D., Stifter, S. and Lavezzi, A.M. (2012) Impacts of exogenously derived nitrogen oxide and sulfur compounds on the structure and function of the vascular endothelium—The link between pregnancy hypertension and later life hypertension. Journal of Hypertension Open Access, 1, 103.
[2] Balla, J., Vercellotti, G.M., Jeney, V., Yachie, A., Varga, Z., Jacob, H.S., Eaton, J.W. and Balla, G. (2007) Heme, heme oxygenase, and ferritin: How the vascular endothelium survives (and dies) in an iron-rich environment. Antioxid Redox Signal, 9, 2119-2137.
[3] Jeney, V., Balla, J., Yachie, A., Varga, Z., Vercellotti, G.M., Eaton, J.W. and Balla, G. (2002) Pro-oxidant and cytotoxic effects of circulating heme. Blood, 100, 879-887.
[4] Maisels, M.J. and Kring, E. (2006) The contribution of hemolysis to early jaundice in normal newborns. Pediatrics, 118, 276-279.
[5] Abbott, N.J., Rönnböck, L. and Hansson, E. (2006) Astrocyte-endothelial interactions at the blood-brain barrier. Nature Reviews Neuroscience, 7, 41-53.
[6] Leung, G. and Moody, A.R. (2010) MR imaging depicts oxidative stress induced by methemoglobin. Radiology, 257, 470-476.
[7] Baysal, E., Monteiro, H.P., Sullivan, S.G. and Stern, A. (1990) Desferrioxamine protects human red blood cells from hemin-induced hemolysis, Free Radic Biol Med, 9, 5-10.
[8] Mills, E., Dong, X.P., Wang, F. and Xu, H. (2010) Mechanisms of brain iron transport: Insight into neurodegeneration and CNS disorders. Future Medicinal Chemistry, 2, 51.
[9] Brar, S., Henderson, D., Schenck, J. and Zimmerman, E.A. (2009) Iron accumulation in the substantia nigra of patients with Alzheimer’s disease and parkinsonism. JAMA Neurology, 66, 371-374.
[10] Mohorovic, L. (2003) The level of maternal methemoglobin during pregnancy in an air-polluted environment, Environmental Health Perspectives, 111, 1902-1905.
[11] Mohorovic, L. and Micovic, V. (2012) The importance of first blood circulation stage, a new insight into the pathogenesis of clinical manifestations of preeclampsia, Advances in Bioscience and Biotechnology , 3, 945-950.
[12] Mohorovic, L., Materljan, E. and Brumini, G. (2008) Are neonatal jaundice, heart murmur, dyslalia and learning/ memory impairments the consequences of maternal exposure to environmental oxidants? XXIV International Congress Fetus as a Patients, Frankfurt.
[13] Lavezzi, A.M., Mohorovic, L., Alfonsi, G., Corna, M.F. and Matturri, L.L. (2011) Brain iron accumulation in unexplained fetal and infant death victims with smoker mothers—The possible involvement of maternal methemoglobinemia, BMC Pediatrics, 11, 62-67.
[14] Conrad, M.E., Umbreit, J.N., Moore, E.G., Hainsworth, L.N., Porubcin, M., Simovich, M.J., Nakada, M.T., Dolan, K. and Garrick, M.D. (2000) Separate pathways for the cellular uptake of ferric and ferrous iron. American Journal of Physiology: Gastrointestinal and Liver Physiology, 279, 767-774.
[15] Smith, M.A., Harris, P.L.R., Sayre, L.M. and Perry, G. (1997) Iron accumulation in Alzheimer’s disease is a source of redox-generated free radicals, Proceedings of the National Academy of Sciences of the United State of America, 94, 9866-9868.
[16] Perry, G., Taddeo, M.A., Petersen, R.B., Castellani, R.J., Harris, P.L., Siedlak, S.L., Cash, A.D., Liu, Q., Nunomura, A., Atwood, C.S. and Smith, M.A. (2003) Iron and copper are at the center of oxidative damage in Alzheimer’s disease. Biometals, 16, 77-81.
[17] Marlatt, M., Lee, H.G., Perry, G., Smith, M.A. and Zhu, X. (2004) Sources and mechanisms of cytoplasmic oxidative damage in Alzheimer’s disease. Acta Neurobiologiae Experimentalis (Warsaw), 64, 81-87.
[18] Honda, K., Smith, M.A.,, Zhu, X., Baus, D., Merrick, W.C., Tartakoff, A.M., Hattier, T., Harris, O.L. Siedlak, S-L., Fujioka, H., Liu, K., Moreira, P.I., Miller, F.P., Nunomura, A., Shimohama, S. and Perry, G., (2005) Ribosomal RNA in Alzheimer’s disease is oxidized by bound redox-active iron. The Journal of Biological Chemistry, 280, 20978-20986.
[19] Circu, M.L. and Aw, T.Y. (2010) Reactive oxygen species, cellular redox systems, and apoptosis. Free Radical Biology & Medicine, 48, 749-762.
[20] Jacob, A.K., Hotchkis, R.S., DeMeester, S.L., Hiramatsu, M., Karl, I.E., Swanson, P.E., Cobb, J.P. and Buchman, T.G. (1997) Endothelial cell apoptosis is accelerated by inorganic iron and heat via an oxygen radical dependent mechanism, Surgery, 122, 243-253.
[21] Vymazal, J., Brooks, R.A., Patronas, N., Hajek, M., Bulte, J.W. and Di Chiro, G. (1995) Magnetic resonance imaging of brain iron in health and disease. Neurological Sciences, 134, 1926.
[22] Schenk, J.F. and Zimmerman, E.A. (2004) High-field magnetic resonance imaging of brain iron: Birth of a biomarker? NMR in Biomedicine, 17, 433-445.
[23] Rouault, T.A. and Cooperman, S.S, (2006) Brain iron metabolism, Seminars in Pediatric Neurology, 13, 142-148.
[24] Gálvez, N., Fernández, B., Sánchez, P., Cuesta, R., Ceolín, M., Clemente-León, M., Trasobares, S., López-Haro, M., Calvino, J.J., Stéphan, O. and Domínguez-Vera J.M. (2008) Comparative structural and chemical studies of ferritin cores with gradual removal of their iron contents. Journal of the American Chemical Society, 130, 8062-8068.

Copyright © 2021 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.