Effects of chronic dietary aluminum on local cerebral glucose utilization in rats.

Beginning at 4 weeks of age normal, male, Sprague-Dawley rats were reared on Purina Laboratory Chow and drinking water containing 100 microM AlCl3. After 2 years, local rates of cerebral glucose utilization were determined with the autoradiographic [14C] deoxyglucose method in the brain as a whole and in 25 brain regions in 6 treated rats and 4 age-matched controls. The results indicate that any effects of chronic aluminum in the diet on rates of cerebral glucose utilization are small. In the brain as a whole, the mean rate of glucose utilization in the aluminum-treated rats was 6% lower than that of the controls (p = 0.09). In 21 of the 25 brain regions examined mean rates of glucose utilization were generally lower in the aluminum-treated rats but in none of the region were the effects statistically significant.

Iron and aluminum homeostasis in neural disorders.

The brain is the most compartmentalized organ. It is also highly aerobic. Because nerve cells grow but do not regenerate, the brain is the organ best suited for the accumulation of metabolic errors colocalized in specific areas of the brain over an extended period. Alzheimer's disease (AD) is primarily a neurological disorder of the elderly. It is suggested that this disorder results from the accumulation of such errors, and that AD onset aluminum and iron contribute to but do not necessarily initiate the onset of the disease. In vitro and in vivo evidence summarized here suggests that this is effected by interfering in the utilization of glucose and glucose-6-phosphate, and sequestration of iron by ferritin. beta-amyloid precusor proteins (beta-APPs) are normal components of the human brain and some other tissues. Proteolysis of these, presumably by serine proteases, generates a 39 to 42 amino acid long peptide, the alpha-amyloid (beta-AP). In AD brains, beta-AP aggregates into plaque, the hallmark of AD brains. Some of the alpha-APPs also contain a 56 amino acid long segment which inhibits serine proteases. We show that in vitro, at pH 6.5, aluminum activates beta-chymotrypsin 2-fold and makes it dramatically resistant to protease inhibitors such as bovine pancreatic trypsin inhibitor (bPTI) or its mimic present in the beta-amyloid precursor proteins (beta-APPs). Iron and oxygen are reported to favor cross-linking of beta-AP in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

MR of human postmortem brain tissue: correlative study between T2 and assays of iron and ferritin in Parkinson and Huntington disease.

PURPOSE: To test the hypothesis that the T2 shortening observed on MR images of the brain in patients with Parkinson and Huntington diseases is due to tissue iron deposition. METHODS: Tissue iron and ferritin assays were performed on postmortem putamen and globus pallidus samples from subjects with Huntington and Parkinson disease. The assays were correlated with T2 measurements. Normal samples were included as controls. RESULTS: There were significant differences in T2 values, and iron and ferritin concentrations among the putamen samples. Compared with normal controls, subjects with Huntington disease had approximately a threefold increase in iron and a sixfold increase in ferritin concentrations; however, they also had the longest T2 values. Parkinson disease putamens had milder elevations of iron concentrations above that of controls (33%) and demonstrated slightly shorter T2 values. The globus pallidus samples demonstrated a similar trend in their T2s, iron, and ferritin levels, but there was a larger overlap in the T2 values. CONCLUSIONS: Our results indicate that tissue iron and ferritin concentrations are elevated in the brains of subjects with both Parkinson and Huntington disease but the elevated concentrations do not correlate with T2 shortening. Although iron and ferritin can shorten T2, we conclude that other factors must play a significant role in determining the T2 relaxation time and that iron or ferritin are not dominant in this regard.

Quantification of cardiac and tissue iron by nuclear magnetic resonance relaxometry in a novel murine thalassemia-cardiac iron overload model.

OBJECTIVE: To determine whether nuclear magnetic resonance (NMR) relaxation parameters can be used to quantify iron in tissues, the relationship between NMR spectrometric T2 relaxation measurements and tissue iron concentration were verified in a novel murine cardiac iron overload model. METHODS: Congenital heterozygous thalassemic mice and controls were injected with intraperitoneal iron or saline and were sacrificed at three weeks. Samples of liver, heart and peripheral muscle were subjected to NMR relaxation measurements and continuous distribution analysis. Tissue ferritin levels were determined with immunoadsorbance techniques, and elemental iron was assayed by flame atomic absorption. Tissues were analyzed pathologically with hematoxylin and eosin and Prussian blue staining to confirm the localization of iron. RESULTS: This murine iron loading model was uniquely successful in loading iron into the major organs, especially the heart, and produced significant reductions in T1 and T2 NMR relaxation values. There was a good correlation between soluble ferritin and total iron levels (r=0.92), indicating that there is a constant and significant fraction of total iron present in ferritin irrespective of absolute iron concentrations. Regression analysis between total iron content and T2 relaxivity showed a linear relationship (r=0.96), suggesting that the T2 relaxation parameter is related to tissue iron concentration. The regression relationship suggested that NMR can detect iron levels as low as 0.1 mg/g of tissue. CONCLUSIONS: Parenteral iron loading in mice produces unique iron overload in major organs, including the heart. Local iron deposition is detectable by NMR relaxometry at 0.1 mg/g or higher. There is a linear relationship between iron concentration and T2 relaxivity. Thus, NMR may be an important and useful clinical tool to quantify iron excess in various pathobiological states of human disease due to iron overload, including heart disease.

Ferritin: an iron storage protein with diverse functions.

Ferritin is the major protein for iron storage and iron detoxification. Since non-ferrous metals, such as aluminum, beryllium and zinc, are bound both in vivo and in vitro, ferritin is implicated as a general metal ion donor and detoxicant. The role of ferritin in Al and Be toxicity is discussed. During iron release ferritin produces free radicals which are involved in phosphoprotein inactivation, lipid peroxidation and, possibly, the general aging process. Conversely, during iron loading oxidative energy in the form of electrons and protons is given off. The different subunit compositions of ferritin, termed isoferritins, are, at least in part, involved with the multifunctionality of this protein.

Regulation of serine protease activity by aluminum: implications for Alzheimer disease.

The brain of Alzheimer disease patients contains plaques that are diagnostic for the disease. The plaques also contain beta-amyloid peptide, alpha 1-antichymotrypsin, and the element aluminum. We present indirect evidence that can relate all three components of plaques to each other in such a way as to suggest their involvement in the etiology of the disease. The beta-amyloid peptide is derived by proteolytic processing from beta-amyloid precursor proteins and some of these proteins contain a domain that is highly homologous to bovine pancreatic trypsin inhibitor. Bovine pancreatic trypsin inhibitor also inhibits alpha-chymotrypsin and we show that aluminum affects both the activity and the inhibition of this enzyme. At pH 6.5, in the presence of aluminum, the enzyme activity is doubled, and the inhibitor is only 1% as effective as in the absence of the metal ion. The inhibition by BX-9, a protease inhibitor prepared from protein components of amyloid plaques, is also reduced by aluminum; so too is that by alpha 1-antichymotrypsin but to a lesser degree. In the Alzheimer brain, we propose that aluminum may accelerate proteolytic processing of the beta-amyloid precursor protein by suppression of the inhibitor domain. Thus, the beta-amyloid peptide may accumulate and initiate plaque formation.

T2 values in the human brain: comparison with quantitative assays of iron and ferritin.

Magnetic resonance (MR) imaging with a whole-body imager was performed in 10 fresh, unfixed whole human brains selected randomly from cadavers. All subjects were neurologically intact before death. T2 time constants were measured within the caudate nucleus, putamen, globus pallidus, cortical gray matter, subcortical white matter, and optic radiation. These regions were then excised, and T2 values were measured again with a 1.5-T MR spectrometer. Quantitative assays of iron, ferritin, and protein from these areas were then performed. Iron concentration varied significantly among brain regions, whereas ferritin and protein concentrations were constant among brain regions and among individuals. Neither iron nor ferritin concentration showed any consistent correlation with T2 values. Histologic examination of brain micro-sections with iron- and ferritin-specific stains of demonstrated poor correlation with biochemical assays of ferritin and iron concentrations. Results indicate that T2 values correlate poorly with iron and ferritin concentrations found in neurologically intact brains.