Oligodendrocytes as the Iron Storage Cell in Development

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Oligodendrocytes have the highest iron content of all brain cell types [63-66]. These cells are unique in their capacity to obtain their iron directly through binding the iron storage protein ferritin [67], and may be directly involved in brain iron regulation [68]. In HD, oligodendrocyte production is upregulated and results in increased density of these cells before any clinical symptoms appear [5].

During development, brain ferritin binding coincides with the onset and progression of myelination [33,57,67,69-71] and increasing brain iron levels are a necessary [64,72,73] and integral part of myelin development and differentiation in childhood and early adulthood [8,21,57,74,75]. With age, myelin breakdown becomes an increasing problem, even in healthy individuals [25,29,36,76,77] and continued repairs and remyelination result in increased numbers of oligo-dendrocytes in old age [37]. This 'normal' aging process is essentially what we postulate for the process observed in HD (see Section 2.2) except that abnormal huntingtin causes the process to occur prematurely and thus preferentially impacts early-myelinating regions.

Iron can be translocated between brain regions [78,79]. It is therefore possible that iron released by myelin breakdown [80,81] ultimately contributes to the iron increases observed in gray matter regions and the age-related increased risk of toxicity in these regions (for review see [3,26]). In healthy individuals certain brain regions such as the striatum continue accumulating ferritin iron throughout the lifespan [8,57,59,61] and these increases occur as ferritin iron decreases in white matter regions [61]. In disease states such as HD and AD where myelin breakdown is exacerbated, evidence of lower white matter iron levels are observed in conjunction with abnormally increased iron levels in the striatum (see Figures 2 and 3 in the next section).

3.1.1 Gray and White Matter Oligodendrocyte Density and Iron Levels in Degenerative Brain Diseases

Quantitative studies have shown that human brain gray matter contains substantial numbers of oligodendrocytes. These cells represent approximately 15% (cortex) to 30% (striatum) of total cell bodies in gray matter [4,82,83]. In adults, oligodendrocyte precursors represent an additional 3-5% of gray matter cells [84], but the precursor percentage is likely much higher at younger ages since in humans, childhood and adulthood represent a continuum of oligoden-drocyte development and differentiation [29,37].

In white matter regions oligodendrocytes make up the vast majority (approximately 90%) of cell bodies [85] and the age-related changes as well as the absolute levels of ferritin iron in these regions probably closely reflect changes in the density of oligodendrocytes and their associated myelin as the remaining tissue is composed primarily of axonal cytoplasm [86]. When compared to age-matched normal controls the basal ganglia show increased iron deposits in AD and this increase is even more striking in HD (Figure 2). A large portion of brain iron is associated with myelin [87,88]. It is therefore remarkable that in both HD and AD the iron levels in frontal white matter are lower than in their matched control groups; the opposite pattern from the one seen in the basal ganglia (Figure 2).

The reduction in white matter iron is more striking in HD, reaches statistical significance, and supports published data that suggests a process of myelin breakdown [6-17]. When relaxation rates (a measure of white matter integrity) are examined in the same subject samples that had brain iron levels measured, it is clear that both AD and HD are characterized by loss of myelin integrity (Figure 3). In HD, this observation of myelin breakdown early in the disease process has recently been confirmed using diffusion tensor imaging measures [16].

3.1.2 Iron and Oligodendrocytes in Aging and Huntington's Disease

The striatum is a site of high iron concentrations that increase with age from very low levels at birth ([8,57,59,61], for review see [62]). Several postmortem studies have found markedly increased iron levels in the striatum of patients with HD, suggesting a role for iron in the HD process [8,18,19]. This increase has been confirmed by an in vivo study that also showed the levels to be increased early in the disease process [13].

In early-stage (presymptomatic) HD an increase in the density of oligo-dendrocytes is seen in the striatum before atrophy or loss of neurons [4,5]. Thus the high-iron striatal environment is likely also created early in the disease process [13] since adequate iron levels are essential for oligodendrocyte a)

Brain Regions

Brain Regions

Figure 2. Abnormal ferritin iron levels in (a) Huntington's and (b) Alzheimer's disease versus matched healthy control subjects. FDRI = field dependent relaxation rate increase (an in vivo MRI measure of ferritin iron - see Section 5.1); N = healthy normal control (white); HD = Huntington's disease (light grey); AD = Alzheimer's disease (dark grey). Fwm = frontal lobe white matter; C = caudate; P = putamen; G = globus pallidus. *p < 0.05;**p < 0.01;***p < 0.001 (from [13,21]).

Brain Regions

Figure 2. Abnormal ferritin iron levels in (a) Huntington's and (b) Alzheimer's disease versus matched healthy control subjects. FDRI = field dependent relaxation rate increase (an in vivo MRI measure of ferritin iron - see Section 5.1); N = healthy normal control (white); HD = Huntington's disease (light grey); AD = Alzheimer's disease (dark grey). Fwm = frontal lobe white matter; C = caudate; P = putamen; G = globus pallidus. *p < 0.05;**p < 0.01;***p < 0.001 (from [13,21]).

differentiation and oligodendrocytes and their myelin contain large amounts of iron (reviewed in [26,33,57,67,69-71,87,88]).

Myelin contains ferritin mRNA [89] that is expressed at myelination onset [90] and a large portion of brain iron is associated with myelin [87,88]. As myelin undergoes a process of age-related breakdown [25,29,36,76,77] the released iron may increase risk of toxicity as iron promotes free radical damage ([60,61], for review see [62]) (see Sections 3.5, 3.6, and 4 below).

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AD vs Controls

HD vs Controls

AD vs Controls

Figure 3. Myelin integrity in Alzheimer's and Huntington's disease versus matched healthy control subjects. Fwm = Frontal lobe white matter; R2 = transverse relaxation rate (an in vivo MRI measure of myelin breakdown - see Section 5.1); N = healthy normal control (white); HD = Huntington's disease (light grey); AD = Alzheimer's disease (dark grey). ***p < 0.001 (from [13,21]).

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