HFE gene variants, iron, and lipids: a novel connection in Alzheimer's disease

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.

Keywords: Alzheimer disease; H63D; HFE; brain; cholesterol; iron; sphingolipids.

FIGURE 1

Neuronal acquisition/loss of cholesterol. Cholesterol synthesized by astrocytes is packaged in lipoproteins containing ApoE, released from the cell and taken up by neurons via the lipoprotein receptor-related protein 1 (LRP1)-mediated endocytosis. Cholesterol can be removed by conversion to 24S-hydroxycholesterol, a compound that can cross the BBB, by the action of cholesterol 24-hydroxylase.

FIGURE 2

Total brain cholesterol content of mice expressing WT- or H67D-HFE. Brains were dissected from mice at 6, 12, 18, and 24 months. After homogenization, protein concentration was determined by Bradford assay (n = 7–17 per group including both male and female mice). Lipids were extracted from 100 μl of brain homogenate. Cholesterol content was measured by following the manufacturer’s protocol (Biovision), and is shown as μg of cholesterol per mg of protein (***p < 0.001). Data were analyzed using a two-way ANOVA followed by Bonferroni tests to compare effects of age and genotype on age-related changes in brain cholesterol of HFE variant mice using Graphpad (Prism) software. Error bars represent the standard error of the mean.

FIGURE 3

Effects of the expression H63D-HFE and how they may lead to AD. We propose that (1) the increase in brain iron induced by the expression of H63D-HFE is initially compensated for by an elevation in brain cholesterol. (2) The elevated iron and cholesterol then synergistically enhance Aβ accumulation and together induce oxidative stress and lipid peroxidation. As the cycle of increased iron, increased Aβ and inhibition of cholesterol synthesis continues, the levels of oxidative radicals supersede the cell’s antioxidant capacity. This affects mitochondrial function, enhances secretion of inflammatory cytokines and other toxic radicals, increases tau phosphorylation, intracellular Ca²⁺, and GM1. (3) As iron accumulation and the concomitant changes it induces occur they start to alter expression of enzymes involved in cholesterol metabolism thereby reducing its concentration. (4) In an effort to survive, cells adapt to a state of low cholesterol content in an effort to limit Aβ production. (5) Over time, due to decreased cholesterol and damage induced by oxidative radicals and other changes, myelin and eventually synapses disintegrate leading to cell death. The resultant neuronal loss would then impair memory function culminating in AD.