Iron Deficiency and Excess in the Brain: Implications for Cognitive Impairment and Neurodegeneration

Abstract

• Iron is a two-way sword. Either its brain iron deficiency (ID) or excess profoundly affects brain function. • ID can result in reduction of brain iron by roughly 35% as contrast to a 90% depletion in the liver. Thus it is tightly controlled. It is associated with impairment of cognition and learning processes which may result from alteration in dopaminergic, at the level of its receptor subsensitivity, and increased opiate neurotransmission. Other aminergic systems are not profoundly affected. • The effect of ID on brain function is age dependent, and it is more severe in newborn rats than adults and is irreversible in newborn even after long-term supplementation with iron. • The exact mechanisms by which dopamine receptors are affected by ID and their effects cognition are not well understood, but may involve dopamine interaction with the endogenous opiates, enkephalin, and dynorphins, involving the hippocampus and striatum. • One of the major findings on brain iron metabolism is its accumulation at neuronal sites which degenerate and give rise to neurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease, Huntington’s diseases. Some are familial disorders, with mutation of genes involved in iron metabolism, such as Freidreich’s ataxia, PANK2, aceruloplasminemia. • The role of iron and its accumulation in substantia nigra pars compacta of parkinsonian brains, where melanized dopamine neuron selectively degenerates, has indicated that iron participates in the Fenton reaction to induce oxidative stress-dependent damage to the neurons. • Confirmation for participation of iron in Parkinson’s disease has come from its 6-hydroxydopmaine, MPTP (N-methy-4-phenyl-1,2,3,6-tetrahydropyridine), and lactacystin neurotoxin models, where similar iron accumulation occurs in substantia nigra pars compacta and pretreatment with iron chelators are neuroprotective. Several iron chelators have been developed as neuroprotective agents for Parkinson’s disease and other neurodegenerative disorders. • It is apparent that iron accumulation may have a pivotal role in the degeneration of dopamine neurons in Parkinson’s disease. Future studies must illuminate why the process of neurodegeneration results in iron deposition and from where it is transported when it has limited access across the blood–brain barrier.