Aluminum Disruption of Calcium Homeostasis and Signal Transduction Resembles Change that Occurs in Aging and Alzheimer's Disease

Abstract

Most humans living in industrialized societies are routinely exposed to bioavailable aluminum salts in the form of additives-in commercially-prepared foods, alum-clarified drinking water, certain pharmaceuticals, sunscreens, and other topical applications. Minute amounts of this aluminum are absorbed into the circulation. Trace aluminum levels cross the blood-brain barrier and progressively accumulate in large pyramidal neurons of the hippocampus, cortex, and other brain regions vulnerable in Alzheimer's disease. More aluminum enters the brain than leaves, resulting in a net increase in intraneuronal aluminum with advancing age. Aluminum is responsible for two main types of toxic damage in cells. As a pro-oxidant, aluminum causes oxidative damage both on its own and in synergy with iron. Aluminum also competes with, and substitutes for, essential metals-primarily Mg2+, iron and Ca2+ ions-in or on proteins and their co-factors. The author hypothesizes that intraneuronal aluminum interferes with Ca2+ metabolism in the aged brain and describes a way to test this hypothesis. This paper reviews: 1) major changes that occur in brain Ca2+ homeostasis and Ca2+ signaling, subtly with aging and more overtly in Alzheimer's disease; and 2) evidence from the scientific literature that aluminum causes these same changes in neurons.

Systematic review of potential health risks posed by pharmaceutical, occupational and consumer exposures to metallic and nanoscale aluminum, aluminum oxides, aluminum hydroxide and its soluble salts

“…The AD and Al literatures remain linked in reports from some researchers (Bondy 2010, Campdelacreu 2012, Tomljenovic 2011, Walton 2012b) yet others conclude factors distinct from Al are responsible for AD (reviewed in Lidsky 2014, Willhite et al 2012). A primary feature of AD pathogenesis is β-amyloid precursor protein (APP) catabolism by the actions of α-and β-secretase that yield the amyloid β-peptides (Aβ).…”

“…With respect to the Al hypothesis for AD (Graves et al 1990, Kawahara and Kato-Negishi 2011, Krewski et al 2007, Perl and Moalem 2006, Rusina et al 2011, Tomljenovic 2011, Walton 2010, 2012a, 2012b), it remains unclear why Al welders and other Al workers (Akila et al 1999, Giorgianni et al 2012, Graves et al 1998, Gun et al 1997, Hanninen et al 1994, Rossbach et al 2006, Salib and Hillier 1996, Santibáñez et al 2007) or people who experience very high prolonged Al exposures via PN, renal dialysis, and/or Al phosphate binders (Jenkins et al 1989, Klein et al 1984, Ott et al 1982, Pei et al 1992, 1995, Salusky et al 1984, 1990, 1991, Smith et al 1986) who accumulate substantial Al body burdens (serum Al 30–40 to ≥ 100 μg/L) and who show clinical signs of Al intoxication do not experience elevated AD risk.…”

The meaning of aluminium exposure on human health and aluminium-related diseases

“…These transporters often mediate the uptake of multiple metal ions. Data on tissue aluminium content from patients with chronic renal insufficiency, treated for long periods with dialysis, show high levels of aluminium in the brain, clearly demonstrating the ability of this metal to penetrate the BBB (76,77) . Also, in this case, the intimate mechanisms by which aluminium ions cross the BBB are not well known.…”

“…In a recent review on the effects of chronic exposure of the human brain to aluminium ions, the ability of aluminium ions to substitute essential metals such as Mg II , Fe II and Ca II ions in intraneuronal proteins was underlined. On the basis of these data, the author hypothesised that aluminium might disrupt calcium homeostasis in human neurons with remarkable signal transduction changes, as frequently observed in Alzheimer ' s disease patients (77) . The intimate mechanism of aluminium-induced neurotoxicity has been recently linked to the accumulation of iron and to the production of reactive oxygen species, suggesting that aluminium-induced neurodegeneration could be halted by chelating excess iron (91) .…”

Inhibition of Cartilage Acidic Protein 1 Reduces Ultraviolet B Irradiation Induced-Apoptosis through P38 Mitogen-Activated Protein Kinase and Jun Amino-Terminal Kinase Pathways

“…Both abnormal Ca 2+ levels and inappropriate Ca 2+ signaling are related to many clinical disorders such as stroke, obesity, cardiac dysfunction, aging and Alzheimer's disease [22][23][24][25]. It is worth noting that Ca 2+ signaling is a key element of apoptotic signaling pathways.…”