A Quantitative Analysis of Isoferritins in Select Regions of Aged, Parkinsonian, and Alzheimer's Diseased Brains

Abstract

The brain requires a ready supply of iron for normal neurological function, but free iron is toxic . Consequently, iron bioavailability must be stringently regulated . Recent evidence has suggested that the brain iron regulatory system is dysfunctional in neurological disorders such as Alzheimer's and Parkinson's diseases (AD and PD, respectively) . A key component of the iron regulatory system in the brain is ferritin . Ferritin consists of 24 subunits, which are distinguished as either a heavy-chain (H) or light-chain (L) isoform . These peptide subunits are genetically and functionally distinct . Thus, the ability to investigate separately the types of ferritin in brain should provide insight into iron management at both the cellular and the molecular level . In this study, the ratio of isoferritins was determined in select regions of adult elderly AD and PD human brains . The H-rich ferritin was more abundant in the young brain, except in the globus pallidus where the ratio of H/L ferritin was 1 :1 . The balance of H/ L isoferritins was influenced by age, brain region, and disease state . With normal aging, both H and L ferritin increased ; however, the age-associated increase in isoferritins generally failed to occur in AD and PD brain tissue . The imbalance in H/L isoferritins was disease and region specific . For example, in frontal cortex, there was a dramatic (fivefold) increase in the ratio of H/L ferritin in AD brains but not in PD brains . In PD, caudate and putamen H/L ratios were higher than in AD and the elderly control group . The analysis of isoferritin expression in brain provides insight into regional iron regulation under normal conditions and suggests a loss of ability to maintain iron homeostasis in the two disease states. This latter observation provides further evidence of dysfunction of iron homeostatic mechanisms in AD and PD and may contribute significantly to understanding the underlying pathogenesis of each, particularly in relation to iron-induced oxidative damage . Key Words : Neurological disorders-Oxidative damage-Iron-CNS-Basal ganglia . J. Neurochem. 65, 717-724 (1995) .Ferritin is the major iron storage protein and consists of different ratios of predominantly two isoforms . The

Biology of ferritin in mammals: an update on iron storage, oxidative damage and neurodegeneration

“…The overall increase in ferritin seems to exceed that of iron, at least in the hippocampus of AD patients, hence most iron should be ferritin-bound (Galazka-Friedman et al 2004), thus in a safe state. Interestingly a quantitative analyses of isoferritins in the brain of controls and AD patients found region and disease specific alteration of the balance between H and L subunits, with the L subunit concentration being lower in the cortex and in the SN of AD brain (Connor et al 1995); a proteomic analysis of AD hippocampi also found elevated H-chain levels (Sultana et al 2007). As observed in different experimental systems, this imbalance could be associated with an abnormal iron management by ferritin itself.…”

“…The amount of the metal increases with aging (Bartzokis et al 1999;Zecca et al 2005), but this is not necessarily linked to pathological alteration or dysfunction of the brain; a parallel increase of ferritins is actually observed in normal aging (Connor et al 1995) that should guarantee the safe storage and handling of the metal. Local siderosis has been linked to different neurodegenerative disorders, including Alzheimer's (AD) and Parkinson's disease (PD); however its clinical relevance and its role in the pathogenesis are largely unraveled; on one hand iron accumulation could be associated to excess labile iron that could play a causative or exacerbating role in disease development by increasing ROS generation, on the other hand its deposition may be simply an epiphenomenon of cell death due to other unrelated causes.…”

“…The hypothesis of an increase of iron in the SN of patients is generally accepted and documented (Sofic et al 1988;Dexter et al 1989;Oakley et al 2007), even though the difference between controls and PD samples appears to be affected by factors such as disease severity, gender or age of onset (Snyder and Connor 2009). Less clear are the modification of ferritin levels, with studies showing an increase (Sofic et al 1988;Licker et al 2014), a decrease (Dexter et al 1990;Connor et al 1995;Faucheux et al 2002) or changes in the relative H/L ratio (Koziorowski et al 2007), with consequent functional implication for iron handling. The loss of neurons (rich in H subunit), the reactive gliosis (microglial cells are rich in L ferritin) as well as technical aspects such as the type of antibodies applied for IHC may be important confounding factor in this analysis (Snyder and Connor 2009).…”

Age-Related Changes in Iron Homeostasis and Cell Death in the Cerebellum of Ceruloplasmin-Deficient Mice

“…Previous studies have reported that iron accumulates in the human CNS with normal aging (Hallgren and Sourander, 1958;Connor et al, 1995;Zecca et al, 2001). This accumulation of iron occurs in astrocytes and microglia in the cerebral cortex, cerebellum, hippocampus, basal ganglia, and amygdala in people between 60 and 90 years of age (Connor et al, 1990).…”

Heme Regulation in Traumatic Brain Injury: Relevance to the Adult and Developing Brain

“…Whether or not this relatively lower level of expression confers vulnerability is not clear. Ferritin expression is prolonged in microglia; whereas, its expression is delayed in oligodendrocytes after neonatal hypoxia/ischemia (Cheepsunthorn et al, 2001;Connor et al, 1995b). This most likely accounts for the shift in iron staining from oligodendrocytes to microglia in the injured immature brain.…”