Abstract
Iron accumulation and associated oxidative stress in the brain have been consistently found in several neurodegenerative diseases. Multiple genetic studies have been undertaken to try to identify a cause of neurodegenerative diseases but direct connections have been rare. In the iron field, variants in the HFE gene that give rise to a protein involved in cellular iron regulation, are associated with iron accumulation in multiple organs including the brain. There is also substantial epidemiological, genetic, and molecular evidence of disruption of cholesterol homeostasis in several neurodegenerative diseases, in particular Alzheimer’s disease (AD). Despite the efforts that have been made to identify factors that can trigger the pathological events associated with neurodegenerative diseases they remain mostly unknown. Because molecular phenotypes such as oxidative stress, synaptic failure, neuronal loss, and cognitive decline, characteristics associated with AD, have been shown to result from disruption of a number of pathways, one can easily argue that the phenotype seen may not arise from a linear sequence of events. Therefore, a multi-targeted approach is needed to understand a complex disorder like AD. This can be achieved only when knowledge about interactions between the different pathways and the potential influence of environmental factors on them becomes available. Toward this end, this review discusses what is known about the roles and interactions of iron and cholesterol in neurodegenerative diseases. It highlights the effects of gene variants of HFE (H63D- and C282Y-HFE) on iron and cholesterol metabolism and how they may contribute to understanding the etiology of complex neurodegenerative diseases.
Highlights
The average increase in life expectancy has been accompanied by an increase in the number of people with dementia, a problem expected to affect half of those living to be 85 or older
The observations that more than 40% of Alzheimer’s disease (AD) patients carried the ApoE4 allele (Cedazo-Minguez and Cowburn, 2001) and that those carrying both the ApoE4 allele and expressing the H63D variant of the hemochromatosis protein HFE were prone to earlier onset of AD (Moalem et al, 2000; Percy et al, 2008) support the hypothesis that disruption of the normal metabolism of both iron and cholesterol contribute to AD
The need for a discussion of the role of iron and cholesterol in neurodegenerative disease stems from our observation that disruption of normal iron metabolism in H63D-HFE-expressing human neuroblastoma cells resulted in altered cholesterol metabolism as well as our findings that mice expressing the orthologous H67D-HFE had alterations in brain iron and cholesterol metabolism and a reduction in brain volume that correlated with poorer recognition and spatial memory, symptoms associated with AD (Ali-Rahmani et al, 2014a)
Summary
The average increase in life expectancy has been accompanied by an increase in the number of people with dementia, a problem expected to affect half of those living to be 85 or older. In addition to the increased iron accumulation seen in cells expressing H63D-HFE (Lee et al, 2007; Mitchell et al, 2009b), disruption of mitochondrial potential (Lee et al, 2007), increased influx of intracellular Ca2+ (Mitchell et al, 2009b), increased glutamate uptake (Mitchell et al, 2009b), increased secretion of monocyte chemoattractant protein-1 (MCP1) that has a role in neuroinflammation (Mitchell et al, 2009a), increased ER stress (Liu et al, 2011), increased oxidative stress (Lee et al, 2007), increased toxicity to Aβ (Mairuae et al, 2010), and decreased Pin activity (Hall et al, 2010) that contributes to increased Tau phosphorylation (Hall et al, 2011) are found These findings demonstrate that the expression of H63D-HFE creates a permissive milieu for processes that can influence other pathways in neuronal cells such as lipid homeostasis, neurotransmission, and myelination that may lead to AD
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