Characterization of an NF-kappaB-regulated, miRNA-146a-mediated down-regulation of complement factor H (CFH) in metal-sulfate-stressed human brain cells.

Micro RNAs (miRNAs) represent a family of small ribonucleic acids (RNAs) that are post-transcriptional regulators of messenger RNA (mRNA) complexity. Brain cells maintain distinct populations of miRNAs that support physiologically normal patterns of expression, however, certain miRNA abundances are significantly altered in neurodegenerative disorders such as Alzheimer's disease (AD). Here we provide evidence in human neural (HN) cells of an aluminum-sulfate- and reactive oxygen species (ROS)-mediated up-regulation of an NF-kappaB-sensitive miRNA-146a that down-regulates the expression of complement factor H (CFH), an important repressor of inflammation. This NF-kappaB-miRNA-146a-CFH signaling circuit is known to be similarly affected by Abeta42 peptides and in AD brain. These aluminum-sulfate-inducible events were not observed in parallel experiments using iron-, magnesium-, or zinc-sulfate-stressed HN cells. An NF-kappaB-containing miRNA-146a-promoter-luciferase reporter construct transfected into HN cells showed significant up-regulation of miRNA-146a after aluminum-sulfate treatment that corresponded to decreased CFH gene expression. These data suggest that (1) as in AD brain, NF-kappaB-sensitive, miRNA-146a-mediated, modulation of CFH gene expression may contribute to inflammatory responses in aluminum-stressed HN cells, and (2) underscores the potential of nanomolar aluminum to drive genotoxic mechanisms characteristic of neurodegenerative disease processes.

[1]  Lucila Aimo,et al.  Aluminium and lead: molecular mechanisms of brain toxicity , 2008, Archives of Toxicology.

[2]  Charles N Serhan,et al.  A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease. , 2005, The Journal of clinical investigation.

[3]  C. Exley.  Aluminium and iron, but neither copper nor zinc, are key to the precipitation of beta-sheets of Abeta_{42} in senile plaque cores in Alzheimer's disease. , 2006, Journal of Alzheimer's disease : JAD.

[4]  D. Baltimore,et al.  NF-κB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses , 2006, Proceedings of the National Academy of Sciences.

[5]  C. Caruso,et al.  Immunological and immunogenetic markers in sporadic Alzheimer’s disease , 2006, Aging clinical and experimental research.

[6]  W. Lukiw,et al.  Induction of specific micro RNA (miRNA) species by ROS-generating metal sulfates in primary human brain cells. , 2007, Journal of inorganic biochemistry.

[7]  W. Lukiw.  Gene Expression Profiling in Fetal, Aged, and Alzheimer Hippocampus: A Continuum of Stress-Related Signaling , 2004, Neurochemical Research.

[8]  M. Molaschi,et al.  Early re-hospitalization of elderly people discharged from a geriatric ward , 2006, Aging clinical and experimental research.

[9]  W. Lukiw,et al.  Nanomolar aluminum induces pro-inflammatory and pro-apoptotic gene expression in human brain cells in primary culture. , 2005, Journal of inorganic biochemistry.

[10]  Walter J. Lukiw,et al.  An NF-κB-sensitive Micro RNA-146a-mediated Inflammatory Circuit in Alzheimer Disease and in Stressed Human Brain Cells* , 2008, Journal of Biological Chemistry.

[11]  S. Bondy,et al.  Pro-inflammatory effects of aluminum in human glioblastoma cells , 2002, Brain Research.