Aluminum triggers NFκB signalling, inflammatory and apoptotic gene expression in human neural cells

Abstract

Aluminum, the most abundant neurotoxic metal in the biosphere, has been implicated in the etiology of neurodegenerative disorders including Alzheimers disease (AD). To further understand aluminum's influence on brain gene expression we examined 2360 RNA message levels in normal human neural progenitor (NHNP) cells using DNA microarrays. Of the 53 gene expression levels that were altered by a factor of >3‐fold (p < 0.05) over control, 44 were down‐regulated. This group included transcripts encoding 17 transcription factors (TFs) or TF kinases, 12 membrane receptors, genes encoding 10 growth factors, neurotransmitters, DNA ligase, DNA repair enzymes and antiapoptotic factors such as bcl‐2. The only TFs found to be consistently induced by aluminum on these panels were members of the pro‐inflammatory (PI) NFκB gene family. As verified independently by RT–PCR, eight of the nine genes found to be induced by aluminum encoded PI or proapoptotic signalling elements, including NFκB p52/p65, IL‐1 precursor, COX‐2 and DAXX, a FAS binding protein known to induce apoptosis and repress transcription. These PI gene promoters contain multiple NFκB binding sites; electrophoretic mobility shift assay and [kB]4 vector transfection analysis indicated that aluminum strongly induced NFκB‐DNA binding, suggesting a role for aluminum and NFκB in driving PI gene expression in neural cells. Interestingly, many aluminum‐induced PI genes are also elevated in AD. These data show that aluminum triggered NHNP cells emulate many of the gene expression patterns observed in AD including the rampant up‐regulation of NFκB‐sensitive and PI signalling genes.Acknowledgements: Supported in part by NIH AG18031, NS23002 and the EENT Foundation.