Brain Burdens of Aluminum, Iron, and Copper and their Relationships with Amyloid-β Pathology in 60 Human Brains.

Lennard-Jones Laboratories, The Birchall Centre, Keele University, Staffordshire, UK.
Journal of Alzheimer's disease: JAD (Impact Factor: 4.15). 06/2012; 31(4). DOI: 10.3233/JAD-2012-120766
Source: PubMed

ABSTRACT The deposition in the brain of amyloid-β as beta sheet conformers associated with senile plaques and vasculature is frequently observed in Alzheimer's disease. While metals, primarily aluminum, iron, zinc, and copper, have been implicated in amyloidβ deposition in vivo, there are few data specifically relating brain metal burden with extent of amyloid pathologies in human brains. Herein brain tissue content of aluminum, iron, and copper are compared with burdens of amyloid-β, as senile plaques and as congophilic amyloid angiopathy, in 60 aged human brains. Significant observations were strong negative correlations between brain copper burden and the degree of severity of both senile plaque and congophilic amyloid angiopathy pathologies with the relationship with the former reaching statistical significance. While we did not have access to the dementia status of the majority of the 60 brain donors, this knowledge for just 4 donors allowed us to speculate that diagnosis of dementia might be predicted by a combination of amyloid pathology and a ratio of the brain burden of copper to the brain burden of aluminum. Taking into account only those donor brains with either senile plaque scores ≥4 and/or congophilic amyloid angiopathy scores ≥12, a Cu : Al ratio of <20 would predict that at least 39 of the 60 donors would have been diagnosed as suffering from dementia. Future research should test the hypothesis that in individuals with moderate to severe amyloid pathology low brain copper is a predisposition to developing dementia.

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    • "However, observed accumulation of iron in amyloid plaques is reportedly lower in mouse models of AD than in human tissue (Leskovjan et al., 2009; Meadowcroft et al., 2009), and tissue iron concentration has been shown not to correlate with plaque burden in human AD cases (House et al., 2008). This observation was reinforced in study of 60 aged human brains, where it was demonstrated that there is no relationship between tissue iron concentration and congophilic amyloid angiopathy or senile plaque burden (Exley et al., 2012). The formation of spherulites from Aβ42 has been demonstrated in the presence of copper (House et al., 2009), and it is postulated that these structures, which form in vitro and are also observed in human brain tissue, may correspond to the senile plaques with fibrillar structure routinely observed with transmission electron microscopy. "
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    ABSTRACT: There is evidence for iron dysregulation in many forms of disease, including a broad spectrum of neurodegenerative disorders. In order to advance our understanding of the pathophysiological role of iron, it is helpful to be able to determine in detail the distribution of iron as it relates to metabolites, proteins, cells, and tissues, the chemical state and local environment of iron, and its relationship with other metal elements. Synchrotron light sources, providing primarily X-ray beams accompanied by access to longer wavelengths such as infra-red, are an outstanding tool for multi-modal non-destructive analysis of iron in these systems.The micro-and nano-focused X-ray beams that are generated at synchrotron facilities enable measurement of iron and other transition metal elements to be performed with outstanding analytic sensitivity and specificity. Recent developments have increased the scope for methods such as X-ray fluorescence mapping to be used quantitatively rather than semi-quantitatively. Burgeoning interest, coupled with technical advances and beamline development at synchrotron facilities, has led to substantial improvements in resources and methodologies in the field over the past decade. In this paper we will consider how the field has evolved with regard to the study of iron in proteins, cells, and brain tissue, and identify challenges in sample preparation and analysis. Selected examples will be used to illustrate the contribution, and future potential, of synchrotron X-ray analysis for the characterization of iron in model systems exhibiting iron dysregulation, and for human cases of neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Friedreich's ataxia, and amyotrophic lateral sclerosis.
    Frontiers in Pharmacology 08/2014; 5. DOI:10.3389/fphar.2014.00191 · 3.80 Impact Factor
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    • "This evidence suggests that Aβ may act to bind natural ferric forms of iron, before chemically reducing them into pathological ferrous iron phases capable of inducing oxidative stress. In addition to iron, other metals such as aluminium, copper and zinc have been shown to accumulate in areas of AD pathology, with synergies between these metals possibly altering the mechanisms of Aβ/iron interaction [37,38]. "
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    ABSTRACT: For decades, a link between increased levels of iron and areas of Alzheimer's disease (AD) pathology has been recognized, including AD lesions comprised of the peptide β-amyloid (Aβ). Despite many observations of this association, the relationship between Aβ and iron is poorly understood. Using X-ray microspectroscopy, X-ray absorption spectroscopy, electron microscopy and spectrophotometric iron(II) quantification techniques, we examine the interaction between Aβ(1-42) and synthetic iron(III), reminiscent of ferric iron stores in the brain. We report Aβ to be capable of accumulating iron(III) within amyloid aggregates, with this process resulting in Aβ-mediated reduction of iron(III) to a redox-active iron(II) phase. Additionally, we show that the presence of aluminium increases the reductive capacity of Aβ, enabling the redox cycling of the iron. These results demonstrate the ability of Aβ to accumulate iron, offering an explanation for previously observed local increases in iron concentration associated with AD lesions. Furthermore, the ability of iron to form redox-active iron phases from ferric precursors provides an origin both for the redox-active iron previously witnessed in AD tissue, and the increased levels of oxidative stress characteristic of AD. These interactions between Aβ and iron deliver valuable insights into the process of AD progression, which may ultimately provide targets for disease therapies.
    Journal of The Royal Society Interface 03/2014; 11(95):20140165. DOI:10.1098/rsif.2014.0165 · 3.92 Impact Factor
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    • "In a recent study by Exley et al. [34], no statistically significant correlation between brain Fe levels and age was found for a group of 60 elderly individuals (70–103 years old), which may indicate that this trend disappears in very old people. When individuals were grouped by gender, quite similar Fe levels were observed (346 ± 36 ␮g/g for women versus 348 ± 73 ␮g/g for men; p = 0.976), with a lower inter-individual variability in women. "
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    ABSTRACT: The link between brain iron homeostasis and neurodegenerative disease has been the subject of extensive research. There is increasing evidence of iron accumulation during ageing, and altered iron levels in some specific brain regions in neurodegenerative disease patients have been reported. Using graphite furnace atomic absorption spectrometry after microwave-assisted acid digestion of the samples, iron levels were determined in 14 different areas of the human brain [frontal cortex, superior and middle temporal, caudate nucleus, putamen, globus pallidus, cingulated gyrus, hippocampus, inferior parietal lobule, visual cortex of the occipital lobe, midbrain, pons (locus coeruleus), medulla and cerebellum (dentate nucleus)] of n=42 adult individuals (71±12 years old, range: 53-101 years old) with no known history or evidence of neurodegenerative, neurological or psychiatric disorders. It was found that the iron distribution in the adult human brain is quite heterogeneous. The highest levels were found in the putamen (mean±SD, range: 855±295μg/g, 304-1628μg/g) and globus pallidus (739±390μg/g, 225-1870μg/g), and the lowest levels were observed in the pons (98±43μg/g, 11-253μg/g) and medulla (56±25μg/g, 13-115μg/g). Globally, iron levels proved to be age-related. The positive correlation between iron levels and age was most significant in the basal ganglia (caudate nucleus, putamen and globus pallidus). Compared with the age-matched control group, altered iron levels were observed in specific brain areas of one Parkinson's disease patient (the basal ganglia) and two Alzheimer's disease patients (the hippocampus).
    Journal of Trace Elements in Medicine and Biology 08/2013; 28(1). DOI:10.1016/j.jtemb.2013.08.001 · 2.37 Impact Factor
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