Christopher Exley

CAN THE CONTROVERSY OF THE ROLE OF ALUMINUM IN ALZHEIMER'S DISEASE BE RESOLVED? WHAT ARE THE SUGGESTED APPROACHES TO THIS CONTROVERSY AND METHODOLOGICAL ISSUES TO BE CONSIDERED?

Aluminum (Al) is unquestionably neurotoxic in both experimental animals and certain human diseases. Minute quantities injected intracerebrally into rabbits will induce severe neurological symptoms and neuropathological features of neurodegeneration. Hyper-aluminemia often develops in patients with renal failure being treated with intermittent hemodialysis on a chronic basis, and in severe cases results in an encephalopathy. Uremic adults and premature infants not on dialysis treatment also can develop encephalopathy due to Al toxicity, as is the case when large amounts of alum are used as a urinary bladder irrigant. There are many other examples of Al-induced neurotoxicity; however, the question as to whether Al presents a health hazard to humans as a contributing factor to Alzheimers disease is still the subject of debate. Several lines of evidence are presented that have formed the basis of the debate concerning the possible pathogenic role for Al in Alzheimers disease. Important evidence for an Al-Alzheimers causal relationship is the observation by laser microprobe mass analysis (LMMS) of the presence of Al in neurofibrillary tangles, although there are conflicting data on the extent of the Al deposition. The relatively poor sensitivity of some of the analytical instruments available for these challenging in situ microanalyses could explain the discrepant results, although LMMS and perhaps secondary ion mass spectrometry (SIMS) appear to be sufficiently sensitive. Harmonization of the techniques is an essential next step. There is new evidence that exposure to Al from drinking water might result in cognitive impairment and an increased incidence of Alzheimers disease. However, these epidemiological studies have inherent problems that must be scrutinized to determine if an association really does exist. An understanding of a possible enhanced bioavailability of Al in this type of exposure, versus other exposures such as antacid intake or industrial exposure, needs to be considered and explored. There has been one promising clinical trial of the treatment of Alzheimers disease patients with the Al chelator desferrioxamine (DFO). Further studies are needed, and if confirmation is forthcoming then such data could also support an Al-Alzheimers disease link as well as suggesting that DFO offers potential as a therapeutic agent. The possibility that iron might be the offending agent needs to be considered since DFO is a very strong iron chelator. The significance of Al-induced neurofibrillary degeneration in experimental animals should be assessed especially in light of new data showing that this model exhibits abnormally phosphorylated tau protein structures in the neuronal perikarya. Thus the key questions that must be answered before it can be asserted that Al possesses causal relationship to Alzheimers disease, are as follows and are addressed in this present discussion: (1) Are there elevations of the concentration of Al in the brains of Alzheimers disease patients? (2) Is there a relationship between environmental exposure to Al, particularly in drinking water, and an increased risk of Alzheimers disease? (3) Is treatment with DFO a potentially useful therapeutic approach and to what extent might beneficial effects of DFO implicate Al in the etiology of Alzheimers disease? (4) Are there similarities between the experimental animal studies and Alzheimers disease particularly in the development of abnormal forms of tau seen in neurofibrillary tangles? (5) Does Al promote the deposition of the A beta peptide in Alzheimers disease? (6) Does hyperaluminemia associated with long-term hemodialysis treatment induce neurofibrillary degeneration? If the answer to each of these six questions is yes, then does this assert that Al possesses a causal relationship to Alzheimers disease? On the other hand, must all six be met to be able to make this assertion?

The cellular toxicity of aluminium

Aluminium is a serious environmental toxicant and is inimical to biota. Omnipresent, it is linked with a number of disorders in man including Alzheimers disease, Parkinsons dementia and osteomalacia. Evidence supporting aluminium as an aetiological agent in such disorders is not conclusive and suffers principally from a lack of consensus with respect to aluminiums toxic mode of action. Obligatory to the elucidation of toxic mechanisms is an understanding of the biological availability of aluminium. This describes the fate of and response to aluminium in any biological system and is thus an important influence of the toxicity of aluminium. A general theme in much aluminium toxicity is an accelerated cell death. Herein mechanisms are described to account for cell death from both acute and chronic aluminium challenges. Aluminium associations with both extracellular surfaces and intracellular ligands are implicated. The cellular response to aluminium is found to be biphasic having both stimulatory and inhibitory components. In either case the disruption of second messenger systems is observed and GTPase cycles are potential target sites. Specific ligands for aluminium at these sites are unknown though are likely to be proteins upon which oxygen-based functional groups are orientated to give exceptionally strong binding with the free aluminium ion.

Silicon in life : A bioinorganic solution to bioorganic essentiality

Abstract The essentiality of silicon in biota is described from the perspective of the interrelationships between geochemistry, biological evolution and biochemistry. A punctuated, as opposed to continuous, silicon bi-cycle implicates the environmental silicic acid concentration in such seemingly diverse processes as catchment acidification, global warming and chronic disease in man.

The immunobiology of aluminium adjuvants: how do they really work?

Aluminium adjuvants potentiate the immune response, thereby ensuring the potency and efficacy of typically sparingly available antigen. Their concomitant critical importance in mass vaccination programmes may have prompted recent intense interest in understanding how they work and their safety. Progress in these areas is stymied, however, by a lack of accessible knowledge pertaining to the bioinorganic chemistry of aluminium adjuvants, and, consequently, the inappropriate application and interpretation of experimental models of their mode of action. The objective herein is, therefore, to identify the many ways that aluminium chemistry contributes to the wide and versatile armoury of its adjuvants, such that future research might be guided towards a fuller understanding of their role in human vaccinations.

A biogeochemical cycle for aluminium

The elaboration of biogeochemical cycles for elements which are known to be essential for life has enabled a broad appreciation of the homeostatic mechanisms which underlie element essentiality. In particular they can be used effectively to identify any part played by human activities in element cycling and to predict how such activities might impact upon the lithospheric and biospheric availability of an element in the future. The same criteria were the driving force behind the construction of a biogeochemical cycle for aluminium, a non-essential element which is a known ecotoxicant and a suspected health risk in humans. The purpose of this exercise was to examine the concept of a biogeochemical cycle for aluminium and not to review the biogeochemistry of this element. The cycle as presented is rudimentary and qualitative though, even in this nascent form, it is informative and predictive and, for these reasons alone, it is deserving of future quantification. A fully fledged biogeochemical cycle for aluminium should explain the biospheric abundance of this element and whether we should expect its (continued) active involvement in biochemical evolution.

A role for the body burden of aluminium in vaccine-associated macrophagic myofasciitis and chronic fatigue syndrome

Macrophagic myofasciitis and chronic fatigue syndrome are severely disabling conditions which may be caused by adverse reactions to aluminium-containing adjuvants in vaccines. While a little is known of disease aetiology both conditions are characterised by an aberrant immune response, have a number of prominent symptoms in common and are coincident in many individuals. Herein, we have described a case of vaccine-associated chronic fatigue syndrome and macrophagic myofasciitis in an individual demonstrating aluminium overload. This is the first report linking the latter with either of these two conditions and the possibility is considered that the coincident aluminium overload contributed significantly to the severity of these conditions in this individual. This case has highlighted potential dangers associated with aluminium-containing adjuvants and we have elucidated a possible mechanism whereby vaccination involving aluminium-containing adjuvants could trigger the cascade of immunological events which are associated with autoimmune conditions including chronic fatigue syndrome and macrophagic myofasciitis.

An interaction of β-amyloid with aluminium in vitro

We have used circular dichroism spectroscopy to confirm that, in a membrane‐mimicking solvent, AβP(1–40) adopts a partially helical conformation and we have demonstrated the loss of this structure in the presence of physiologically relevant concentrations of aluminium. This is the first evidence of a direct biochemical interaction between aluminium and β‐amyloid and may have important implications for the pathogenesis of Alzheimers disease.

A mechanism for acute aluminium toxicity in fish

Aluminium is acutely toxic to fish in acid waters. The gill is the principal target organ and death is due to a combination of ionoregulatory, osmoregulatory and respiratory dysfunction. The toxic mechanism has hitherto received little direct consideration and is unknown. In this paper the mechanism of acute aluminium toxicity is approached from a chemical perspective. Symptomatic evidence of toxicity is taken from the literature and combined with our own research to elucidate a biochemically sound model to describe a possible mechanism of acute aluminium toxicity in fish. The proposed model delineates the chemical conditions immediately adjacent to the gill surface and emphasizes their importance in aluminiums toxic mode of action. The mechanism is shown to be bipartite. Aluminium binding to functional groups both apically located at the gill surface and intracellularly located within lamellar epithelial cells disrupts the barrier properties of the gill epithelium. The concomitant iono- and osmoregulatory dysfunction results in accelerated cell necrosis, sloughing and death of the fish. The mechanism of epithelial cell death is proposed as a general mechanism of aluminium-induced accelerated cell death.

Severe cerebral congophilic angiopathy coincident with increased brain aluminium in a resident of Camelford, Cornwall, UK

In July 1988, 20 tonnes of aluminium sulphate was discharged by the South West Water Authority into the drinking water supplied to a large region of North Cornwall. Up to 20 000 people were exposed to concentrations of aluminium which were 500–3000 times the acceptable limit under European Union legislation (0.200 mg/l). Although this incident is currently the topic of a government inquiry, nothing is known about its longer-term repercussions on human health. The first neuropathological examination of a person who was exposed and died of an unspecified neurological condition was carried out. A rare form of sporadic early-onset β amyloid angiopathy in cerebral cortical and leptomeningeal vessels, and in leptomeningeal vessels over the cerebellum was identified. In addition, high concentrations of aluminium were found coincident with the severely affected regions of the cortex. Although the presence of aluminium is highly unlikely to be adventitious, determining its role in the observed neuropathology is impossible. A clearer understanding of aluminium’s role in this rare form of Alzheimer’s related disease should be provided by future research on other people from the exposed population as well as similar neuropathologies in people within or outside this group.

The reaction of aluminium with silicic acid in acidic solution: an important mechanism in controlling the biological availability of aluminium?

Abstract The reaction of aluminium (Al) with monomeric silicic acid (Si(OH)4) to form an hydroxyaluminosilicate (HAS) has been well documented over the past 40 or so years. The formation of an aluminium hydroxide template, upon which Si(OH)4 will condense in competition with Al, was demonstrated to be a prerequisite to HAS formation. This initial reaction results in the formation of a slowly aggregating HAS, with a Si:Al ratio of 0.5, in which silicon tetrahedra are bonded to Al octahedra through three SiOAl linkages. We have called this HASA. In solutions in which the concentration of Si(OH)4≥Al HASA acts as a template for the incorporation of further silicon tetrahedra to give a rapidly precipitating HAS (that we have called HASB), with a Si:Al ratio of 1.0, in which up to 50% of the constituent Al has adopted tetrahedral geometry. There are, at present, no reliable constants to describe either the formation or the solubility of these HAS. They are extremely insoluble and are likely to play an important role in the control of the release of Al from the edaphic to the aquatic environment. They may also have an important role in Al homeostasis in biota though the evidence to support this is more tentative.