Iron accumulation brain

Another condition involving ceruloplasmin is aceru-loplasminemia. in this genetic disorder, levels of ceruloplasmin are very low and consequently its ferroxidase activity is markedly deficient. This leads to failure of release of iron from cells, and iron accumulates in certain brain cells, hepatocytes, and pancreatic islet cells. Affected individuals show severe neurologic signs and have diabetes mellitus. Use of a chelating agent or administration of plasma or ceruloplasmin concentrate may be beneficial. 

The progression of human immunodeficiency virus (HIV) towards its more advanced stages is accompanied by increasing body stores of iron. Iron accumulates in macrophages as well as microglia, endothelial cells and myocytes. The iron burden is especially intense in the bone marrow, brain white matter, muscle and liver. Such excesses of iron will enhance oxidative stress, impair several already compromised immune defence mechanisms and directly promote the growth of microbes (Boelaert et ah, 1996). 

Alterations in brain iron metabolism have been reported, resulting in increased iron accumulation in Huntington s disease. This was particularly the case in basal ganglia from patients with HD compared to normal controls. In studies in embryonic stem cells, huntingtin was found to be iron-regulated, essential for the function of normal nuclear and perinuclear organelles and to be involved in the regulation of iron homeostasis. 

There is increasing evidence that iron is involved in several neurodegenera-tive diseases. Conditions such as neuroferritinopathy and Friedreich ataxia are associated with mutations in genes that encode proteins that are involved in iron metabolism. As the brain ages, iron accumulates in regions that are affected in AD and PD. High concentrations of reactive iron can increase... 

Smith MA, Casadesus G, Joseph JA, Perry G (2002b) Amyloid-beta and tau serve antioxidant functions in the aging and Alzheimer brain. Free Radic Biol Med 33 1194-1199 Smith MA, Harris PL, Sayre LM, Perry G (1997a) Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc Natl Acad Sci U S A 94 9866-9868 Smith MA, Hirai K, Hsiao K, Pappolla MA, Harris PL, Siedlak SL, Tabaton M, Perry G (1998) Amyloid-beta deposition in Alzheimer transgenic mice is associated with oxidative stress. J Neurochem 70 2212-2215... 

Aceruloplasminemia is an autosomal recessive disease, which is caused by mutations in the ceruloplasmin (Cp) gene and results in a total absence of Cp in the blood. It is an iron accumulation disorder causing clinical problems in the brain and liver. Cp is a ferroxidase, necessary to convert Fe to Fe so that the iron can be bound to transferrin and mobilized from cells. 

Aceruloplasminemia Ceruloplasmin (ferroxidase-) deficiency Accumulation of iron Liver, brain, pancreas, eye 3q23-q25 604290... 

Figure 2. Brain iron deposition. The image on the left is from a 56-year old patient with aceruloplasminemia. This rare disease is known to lead to iron accumulation in the brain and other tissues. The image shows evidence for heavy accumulation of iron in the caudate nucleus, putamen and globus pallidus. The image on the right is from a 64-year old normal control subject. Both images were taken at 3 tesla using a spin-echo sequence with echo time of 18 ms, a 22 cm square field of view and a 2 mm slice thickness. (Images courtesy of J. F. Schenck and E. A. Zimmerman).

An elucidation of the mechanisms of brain iron homeostasis, as outlined in figure 1, will help our understanding of AD especially since iron binds to Ap-peptide and enhances beta-amyloid toxicity [35-38]. Excess iron accumulation is a consistent observation in the AD brain. As discussed above, patients with hemochromatosis are at risk developing AD at an earlier age [2]. Brain autopsy samples from AD patients have elevated levels of ferritin iron, particularly in the neurons of the basal ganglia [39] and most amyloid plaques contain iron and ferritin-rich cells [40]. Clinically there is a reported decrease in the rate of decline in AD patients who were treated with the intramuscular iron chelator, desferrioxamine [41]. Iron enhances cleavage of the Ap-peptide domain of APP by the metalloprotease alpha secretase [42, 43]. Part of the protective effect of the major cleavage product of APP, APP(s), may derive from its capacity to scavange metals to diminish metal-catalyzed oxidative stress to neuronal cells [44]. APP is, itself, a metalloprotein [4]. 

Once in the serum, aluminium can be transported bound to transferrin, and also to albumin and low-molecular ligands such as citrate. However, the transferrrin-aluminium complex will be able to enter cells via the transferrin-transferrin-receptor pathway (see Chapter 8). Within the acidic environment of the endosome, we assume that aluminium would be released from transferrin, but how it exits from this compartment remains unknown. Once in the cytosol of the cell, aluminium is unlikely to be readily incorporated into the iron storage protein ferritin, since this requires redox cycling between Fe2+ and Fe3+ (see Chapter 19). Studies of the subcellular distribution of aluminium in various cell lines and animal models have shown that the majority accumulates in the mitochondria, where it can interfere with calcium homeostasis. Once in the circulation, there seems little doubt that aluminium can cross the blood-brain barrier. 

The mechanism of AD pathogenesis still remains unclear. However, one mechanism, amyloid (3 (A(3) accumulation, may be due to the disturbance in metal homeostasis in AD brains [Strausak et al., 2001]. A(3 peptides are the major constituents of the amyloid core of senile plaques, which are derived from the amyloid precursor protein (APP) and are secreted into extracelluar spaces. Both APP and A(3 contain a copper-binding domain [Hesse et al., 1994 Atwood et al., 1998]. High concentrations of copper, zinc, and iron have been found within the amyloid deposits in AD brains [Lovell et al., 1998], A(3 peptides can be rapidly precipitated by copper under mildly acidic conditions and by zinc at low physiological (submicromolar) concentrations [Bush et al., 1994], An age-dependent binding between A(3 peptides with excess brain metals (copper, iron, and zinc) induces A(3 peptides to precipitate into metal-enriched plaques [Bush, 2002],... 

Good PF, Olanow CW, Perl DP. 1992a. Neuromelanin-containing neurons of the substantia nigra accumulate iron and aluminum in Parkinson s disease A LAMMA study. Brain Res 593 343-346. 

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