Colocalization of Aluminum and Iron in Nuclei of Nerve Cells in Brains of Patients with Alzheimer's Disease.

Increasing evidence indicates that metal-induced oxidative stress plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). Recently, the presence of 8-hydroxydeoxyguanosine, a biomarker of oxidative DNA damage, was demonstrated in nuclear DNA (nDNA) in the AD brain. Iron (Fe) is a pro-oxidant metal capable of generating hydroxyl radicals that can oxidize DNA, and aluminum (Al) has been reported to facilitate Fe-mediated oxidation. In the present study, we examined the elements contained in the nuclei of nerve cells in AD brains using scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy (SEM-EDS). Our results demonstrated that Al and Fe were colocalized in the nuclei of nerve cells in the AD brain. Within the nuclei, the highest levels of both Al and Fe were measured in the nucleolus. The SEM-EDS analysis also revealed the colocalization of Al and Fe in the heterochromatin and euchromatin in neuronal nuclei in the AD brain. Notably, the levels of Al and Fe in the nucleus of nerve cells in the AD brain were markedly higher than those in age-matched control brains. We hypothesize that the colocalization of Al and Fe in the nucleus of nerve cells might induce oxidative damage to nDNA and concurrently inhibit the repair of oxidatively damaged nDNA. An imbalance caused by the increase in DNA damage and the decrease in DNA repair activities might lead to the accumulation of unrepaired damaged DNA, eventually causing neurodegeneration and the development of AD.

Age-related effects of major and trace element concentrations in rat liver and their mutual relationships.

The concentrations of 22 major and trace elements in livers from rats aging from 5 to 113 weeks old were determined. The rats investigated were the same rats previously reported with respect to 29 elements in bones (femur) and 26 elements in kidneys. The samples were decomposed with high-purity nitric acid and hydrogen peroxide. Seven elements (Na, Mg, P, K, Ca, Fe and Zn) were determined by inductively coupled plasma atomic emission spectrometry (ICP-AES), and 15 elements (Mn, Co, Cu, As, Se, Rb, Sr, Mo, Cd, Sn, Sb, Cs, Ba, Pb and Bi) were determined by inductively coupled plasma mass spectrometry (ICP-MS). Analysis of variance (ANOVA) for age variations indicated that the concentrations of many elements, such as Mg, P, K, Mn, Fe, Cu, Zn, Sr, Mo and Cd, were almost constant across the ages of the rats with the exception of 5 weeks old (p > 0.05). Arsenic, Pb and Bi showed significant increasing trends, while Na and Co showed decreasing trends (p < 0.01). Selenium showed a decreasing trend except at the initial stage of 5-9 weeks old. Calcium, Rb, Sn, Sb, Cs and Ba showed significant age-related variations, but their patterns were not monotonic. The liver clearly contrasts with the kidneys, in which many elements showed significant age-related variations with increasing trends. The concentration ranges of Mg, P, K, Mn, Cu, Zn, and Mo were controlled within 15% across all ages of rats. The homeostasis of the aforementioned elements may be well established in the liver. The toxic elements, such as Cd, Pb and Bi, showed a narrow concentration range among age-matched rats.

The concentrations of major and trace elements in rat kidney: aging effects and mutual relationships.

The concentrations of 26 major to trace elements in rat kidneys aging from 5 to 113 weeks old were determined. The rats investigated were the same rats used previously reported to have 29 elements in bones (femurs). The samples were decomposed by high purity nitric acid and hydrogen peroxide. Eight elements (Na, Mg, Si, P, K, Ca, Fe and Zn) were determined using inductively coupled plasma atomic emission spectrometry (ICP-AES) and 18 elements (Mn, Co, Ni, Cu, As, Se, Rb, Sr, Mo, Cd, Sn, Sb, Cs, Ba, Tl, Pb, Bi and U) were determined using inductively coupled plasma mass spectrometry (ICP-MS). The aging effects on the concentrations of these elements and mutual elemental relationships were investigated. Analysis of variance (ANOVA) for age variations indicated that the concentrations of P, K, Mn and Mo were almost constant across the age of rats (p>0.3). The concentration of many elements such as Na, Mg, Ca, Fe, Co, Cu, Zn, As, Se, Cd, Sn, Sb, Tl, Pb and Bi, showed significant increasing trends (p<0.01) with different patterns. Rubidium, Cs, Pb and Bi showed significant age variations but not monotonic trends. Silicon, Ni, Sr, Ba and U showed large concentration scatterings without any significant trends (p>0.01). The metabolism of these elements may not be well established in the kidney. Many toxic elements such as As, Cd, Sn, Pb and Bi showed a narrow concentration range among age-matched rats. The kidney may have established metabolic mechanisms to confine or accumulate these toxic elements even though their concentrations are very low (e.g., 10 ngg(-1) of Cd). These elements also closely coupled with Fe. A cluster analysis was performed using an elemental correlation matrix and indicated that these elements, including Fe, formed a cluster. However, another cluster analysis using "an aging effect eliminated" elemental correlation showed different clustering in which the Fe, Cd cluster disappeared.

Aging effects of major and trace elements in rat bones and their mutual correlations.

The concentrations of 29 major to trace elements in rat bones (femur) aging from 5 to 113 weeks old were determined. The samples were decomposed by high purity nitric acid and hydrogen peroxide. Nine elements (Na, Mg, P, K, Ca, Fe, Ni, Zn, and Sr) were determined by inductively coupled plasma atomic emission spectrometry (ICP-AES) and 20 elements (Li, B, Al, V, Cr, Mn, Cu, As, Se, Rb, Mo, Ag, Cd, Sb, Cs, Ba, W, Tl, Pb, and U) were determined by inductively coupled plasma mass spectrometry (ICP-MS). Aging effects on these elements and mutual elemental correlations were investigated. The concentrations of Ca, P and Na increased in the initial stage of 5-17 weeks and then maintained constant values, whereas those of Mg, K, Mn, Sr and Ba showed decreasing trends of differing patterns. Furthermore, Cu, Zn and Mo showed increasing trends for a whole range of ages. Selenium showed a remarkable increasing trend with a factor of 10. The values of Na, Mg, P, K, Ca, Mn, Cu, Zn, Se and Mo in the age-matched rats distributed narrow ranges, indicating that the metabolism of these elements in bone was well-established. By contrast, those of Al, V, Ni, Ag, Cd, Sb, W, Tl, and U were distributed across a broad range. The metabolism of these elements was not well-established. A cluster analysis was performed using an elemental correlation matrix.

Demonstration of aluminum in amyloid fibers in the cores of senile plaques in the brains of patients with Alzheimer's disease.

Aluminum (Al) exposure has been reported to be a risk factor for Alzheimer's disease (senile dementia of Alzheimer type), although the role of Al in the etiology of Alzheimer's disease remains controversial. We examined the presence of Al in the Alzheimer's brain using energy-dispersive X-ray spectroscopy combined with transmission electron microscopy (TEM-EDX). TEM-EDX analysis allows simultaneous imaging of subcellular structures with high spatial resolution and analysis of small quantities of elements contained in the same subcellular structures. We identified senile plaques by observation using TEM and detected Al in amyloid fibers in the cores of senile plaques located in the hippocampus and the temporal lobe by EDX. Phosphorus and calcium were also present in the amyloid fibers. No Al could be detected in the extracellular space in senile plaques or in the cytoplasm of nerve cells. In this study, we demonstrated colocalization of Al and beta-amyloid (Abeta) peptides in amyloid fibers in the cores of senile plaques. The results support the following possibilities in the brains of patients with Alzheimer's disease: Al could be involved in the aggregation of Abeta peptides to form toxic fibrils; Al might induce Abeta peptides into the beta-sheet structure; and Al might facilitate iron-mediated oxidative reactions, which cause severe damage to brain tissues.

26Al incorporation into the brain of suckling rats through maternal milk.

Aluminium inhibits prenatal and postnatal brain development. However, aluminium incorporation into the brain of sucklings through maternal milk has not yet been well clarified because aluminium lacks a suitable isotope for radioactive tracer experiments. Using 26Al (26AlCl(3)) as a tracer, we measured 26Al incorporation into the brain of suckling rats by accelerator mass spectrometry. Lactating rats were subcutaneously injected with 26AlCl(3) from day 1 to day 20 postpartum. Suckling rats were weaned from day 21 postpartum. From day 5 to day 20 postpartum, the amounts of 26Al measured in the cerebrum, cerebellum, spinal cord, liver, and kidneys of suckling rats increased significantly. After weaning, the amounts of 26Al in the liver and kidneys decreased remarkably. Alternatively, in the cerebrum, cerebellum, and spinal cord, as much as 12 to 20% of the 26Al amounts present on day 20 postpartum remained in the tissues on day 730 postpartum. As the life span of rats is about 2 years, we conclude that considerable amounts of the 26Al taken up into the brain of suckling rats through maternal milk remained in their brain throughout their lifetime.