Synergistic effects of iron and aluminum on stress-related gene expression in primary human neural cells

Issue title: Dedicated to Prof. Marino Nicolini

Article type: Research Article

Authors: Alexandrov, Peter N.^a | Zhao, Yuhai^b | Pogue, Aileen I.^b | Tarr, Matthew A.^d | Kruck, Theo P.A.^e | Percy, Maire E.^e | Cui, Jian-Guo^b | Lukiw, Walter J.^{b; c; *}

Affiliations: [a] Russian Academy of Medical Sciences, Moscow 113152, Russia | [b] Neuroscience Center, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA | [c] Department of Ophthalmology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA | [d] Department of Chemistry, University of New Orleans, New Orleans, LA 70148, USA | [e] Neurogenetics Laboratory, Surrey Place Centre and Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada

Correspondence: [*] Corresponding author: Walter J. Lukiw, MS, PhD, Associate Professor of Molecular Biology and Human Genetics, LSU Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, 2020 Gravier Street, Suite 8B8, New Orleans LA 70112-2272, USA. E-mail: [email protected].

Abstract: Disturbances in metal-ion transport, homeostasis, overload and metal ion-mediated catalysis are implicated in neurodegenerative conditions such as Alzheimer's disease (AD). The mechanisms of metal-ion induced disruption of genetic function, termed genotoxicity, are not well understood. In these experiments we examined the effects of non-apoptotic concentrations of magnesium-, iron- and aluminum-sulfate on gene expression patterns in untransformed human neural (HN) cells in primary culture using high density DNA array profiling and Western immunoassay. Two week old HN cells were exposed to low micromolar magnesium, iron, or aluminum for 7 days, representing trace metal exposure over one-third of their lifespan. While total RNA yield and abundance were not significantly altered, both iron and aluminum were found to induce HSP27, COX-2, βAPP and DAXX gene expression. Similarly up-regulated gene expression for these stress-sensing, pro-inflammatory and pro-apoptotic elements have been observed in AD brain. The combination of iron and aluminum together was found to be particularly effective in up-regulating these genes, and was preceded by the evolution of reactive oxygen intermediates as measured by 2',7'-dichlorofluorescein diacetate assay. These data indicate that physiologically relevant amounts of iron and aluminum are capable of inducing Fenton chemistry-triggered gene expression programs that may support downstream pathogenic responses and brain cell dysfunction.

Keywords: Aluminum sulfate, Alzheimer's disease, apoptosis, Fenton chemistry, human neural cells, inflammation, iron sulfate, magnesium sulfate, synergistic effects

DOI: 10.3233/JAD-2005-8204

Journal: Journal of Alzheimer's Disease, vol. 8, no. 2, pp. 117-127, 2005