Elsevier

NeuroToxicology

Volume 52, January 2016, Pages 222-229
NeuroToxicology

Review
Low levels of aluminum can lead to behavioral and morphological changes associated with Alzheimer's disease and age-related neurodegeneration

https://doi.org/10.1016/j.neuro.2015.12.002 Get rights and content

Abstract

Aluminum (Al) is a very common component of the earth's mineral composition. It is not essential element for life and is a constituent of rather inert minerals. Therefore, it has often been regarded as not presenting a significant health hazard. As a result, aluminum-containing agents been used in the preparation of many foodstuffs processing steps and also in elimination of particulate organic matter from water. More recently, the reduced pH of bodies of water resulting from acid rain has led to mobilization of aluminum-containing minerals into a more soluble form, and these have thus entered residential drinking water resources. By this means, the body burden of aluminum in humans has increased. Epidemiological and experimental findings indicate that aluminum is not as harmless as was previously thought, and that aluminum may contribute to the inception and advancement of Alzheimer's disease. Epidemiological data is reinforced by indications that aluminum exposure can result in excess inflammatory activity within the brain. Activation of the immune system not initiated by an infectious agent, typifies the aging brain and is even more augmented in several neurodegenerative diseases. The origin of most age-related neurological disorders is generally not known but as they are largely not of genetic derivation, their development is likely triggered by unknown environmental factors. There is a growing and consistent body of evidence that points to aluminum as being one such significant influence. Evidence is presented that reinforces the likelihood that aluminum is a factor speeding the rate of brain aging. Such acceleration would inevitably enlarge the incidence of age-related neurological diseases.

Section snippets

Aluminum in the Environment

Aluminum (Al) is the third most abundant element in the earth's crust (Priest et al., 1988). It was only in 1825 that this metal was isolated in its elemental metallic form by the Danish physicist Hans Oersted (Sigel and Sigel, 1988). Al products have many modern applications. Adding aluminum sulfate and lime to water causes aluminum hydroxide formation, which leads to coagulation of pollutants. This procedure is used widely for water clarification in reservoirs. Al-containing materials are

Transitory exposure to high levels of aluminum can result in neurological disturbance

The possibility of Al salts constituting a risk factor in enhancing the likelihood of neurological disease has been originally raised by a number of clinical studies. Thus, hemodialysis of patients with severe kidney disease has led to toxic levels of Al in the blood, from exposure to aluminum in dialysis fluid and from the administration of high levels of aluminum-containing phosphate binders among patients who cannot excrete it. The resulting aluminum-induced dialysis encephalopathy following

Inflammation is pronounced in the aging brain, and this is further elevated in several neurodegenerative disorders

Aging of the brain is characteristically attended by increased levels of inflammation (David et al., 1997, Sharman et al., 2004). Neuroinflammatory changes become more pronounced during normal aging in spite of the lack of identifiable immune stimuli (Sharman et al., 2008, Lucin and Wyss-Coray, 2009). A further worsening of inflammation appears to contribute to pathogenic changes associated with many age-related neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's

Epidemiological evidence of a relation between aluminum intake and the incidence of Alzheimer's disease

Early reports of the neurotoxicity of Al such as those with dialysis dementia involved relatively brief exposure to high levels of Al. More recently and more controversially, adverse effects of chronic exposures to lower levels of Al have been described. The finding of high levels of Al in the brains of patients with AD relative to controls has been reported [see above] and levels of Al are also found higher in less common neurological disorders including the Guamanian Parkinsonian-ALS complex

Link between aluminum exposure and neurodegenerative conditions other than Alzheimer's disease

The connection between Al and less common neurological disorders is uncertain. Aluminum oxyhydroxide (alum) is widely used as a vaccine adjuvant (Girard, 2005, Sutton et al., 2009, Chang et al., 2010, Alvarez-Soria et al., 2011, Shoenfeld and Agmon-Levin, 2011), and phagocytosed alum particles can accumulate in the brain where they may then be re-solubilized by the acidic pH of lysosomes (Gherardi et al., 2015). Injection of alum into neonatal mice in amounts designed to correlate to those used

Experimental results from animals support a causal relation between aluminum exposure and harmful effects on brain function

Clinical findings on aluminum neurotoxicity, are supported by numerous experimental animal models where systemically administered Al caused behavioral deficits. These include reports of in-coordination (Bowdler et al., 1979), changes in reactivity and neuropathological changes reminiscent of those found with brain aging (Miu et al., 2004).

These studies have entailed treatment with concentrations of Al that are not commonly encountered among human populations. However, other studies that better

Morphological and molecular changes produced in the brain by aluminum

A clear mechanistic understanding of the molecular events underlying Al neurotoxicity remains elusive. Despite the chemical inertness of its salts, there are many potential mechanisms by which Al can promote neurotoxic events (Tomljenovic, 2011). The induction of glial activation and initiation of macrophage responsivity by Al complexes has been frequently described many times (Evans et al., 1992, Gorell et al., 1999, Platt et al., 2001) but the means by which Al salts promote inflammatory

Is the passage of Al from the environment to the brain large enough to justify disquiet?

The issue as to whether human aluminum intake from general environmental sources is sufficient for concern remains contentious. Drinking water can contain up to 2.7 mg Al/l, and foodstuffs up to 730 mg Al/kg (Agency for Toxic Substances and Disease Registry, 2008, Stahl et al., 2011). These estimates do not include sources of unusually high aluminum intake such as antacid, baking powder and some acidic fruit drinks. Overall, around 10 mg/d Al from both water and food sources is estimated to be

Why does the neurological outcome of exposure to environmental levels of aluminum remain contested?

While interest in this topic is ongoing but there is not yet an explicit recognition of the hazards of environmental Al and for the need to take more regulatory action. Examination of the history of lead toxicity can give clues that may aid in comprehending of some of the reasons underlying this failure to reach a “critical takeoff velocity.” Lead has been used in manufacturing for over 3000 years and has been intermittently known to be neurotoxic since 700 B. C. Its prevalence has risen

Conclusions

Although the ability of absorbed aluminum to further the onset and progression of neurodegenerative disease remains unresolved, the following conclusions are relevant and incontrovertible.

  • (i)

    Al is widespread in the environment, ingested by humans and can reach the brain.

  • (ii)

    Short exposure to high levels of Al can lead to clear signs of neurological damage.

  • (iii)

    Levels of basal inflammatory activity within the brain increase with age and this is worsened in many age-related neurodegenerative conditions.

  • (iv)

    Low

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