Journal of Environmental Analytical Chemistry

Ferric Iron Brain Deposition as the Cause, Source and Originator of Chronic Neurodegenerative Diseases

Abstract

Lucijan Mohorovic, Anna Lavezzi, Sanja Stifter, George Perry, Djulija Malatestinic, Vladimir Micovic and Eris Materljan

We want to understand the sources of oxidants as factors in understanding the role they play in the pathogenesis of neurodegeneration, such as Alzheimer’s disease (AD). Our earlier observations pointed to the difference of intracellular iron when it originates from physiological hemoglobin versus pathological methemoglobin degradation, where heme oxygenation of hemoglobin results in ferrous (Fe2+) iron, while methemoglobin catabolism produces ferric (Fe3+) iron. Methemoglobin plays the role of carrier, donor and source of cytotoxic redox-active ferric (Fe3+) iron and also plays a critical role as an originator of neurodegenerative diseases. Environmental toxicity factors determine a permanent intracellular source of redox-active ferric (Fe3+) iron which without ferrous-ferric inversions, ‘in situ’, has a direct impact on the endothelial small vessels of the brain, increasing the rate of capillary endothelial cell apoptosis and possible cross into brain parenchyma, to astrocytes, glia, neurons, and other neuronal cells, to cause greater degeneration. Understanding the transport and neuronal accumulation of ferric (Fe3+) iron, points to how microvessels are organized into a well structured neurovascular unit, with harmful consequences for the brain. Previously our research indicated neonatal jaundice incidence (p=0.034), and heart murmur at a later age (p=0.011), and found that the incidence of children and adults displaying mild disorders such as dyslalia and learning/memory impairments (p=0.002) was significantly higher than in children and adults of mothers lacking methemoglobinemia during pregnancy. Our results point to the consequences of mother-fetal methemoglobinemia caused by environmental oxidants, consequences which not been precisely demonstrated yet. The effects of exogenously induced oxidative stress on the structure and function of the vascular endothelial are direct targets of free hemoglobin and of its oxidative derivative methemoglobin which readily release heme, an abundant source of redox-active iron, and react with sulfur compounds synergy during pregnancy, causing early and late vascular endothelial dysfunction in vital organs and the CNS through ‘neurovascular unit’ damage, which plays a critical role in understanding oxidative stress in the pathogenesis of neurodegeneration. The harmful effects of mother-fetal pregnancy complications include increased brain non-heme ferric iron deposition, which has been confirmed by the results of histochemical research. According to our hypothesis such a process could result in neuronal death in humans, and with ageing, leading finally to hard neurodegenerative brain diseases such as AD, PD and others.