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Regulation of Complement Factor H (CFH) by Multiple miRNAs in Alzheimer’s Disease (AD) Brain

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Abstract

Human brain cells rely on a specific subset of microRNAs (miRNAs or miRs) to shape their gene expression patterns, and this is mediated through microRNA effects on messenger RNA (mRNA) speciation and complexity. In recent studies (a) in short post-mortem interval Alzheimer’ disease (AD) brain tissues versus age-matched controls, and (b) in pro-inflammatory cytokine- and Aβ42 peptide-stressed human neuronal-glial (HNG) cells in primary culture, we have identified several brain-abundant miRNA species found to be significantly up-regulated, including miR-125b and miR-146a. Both of these nuclear factor kappa B (NF-κB)-activated, 22 nucleotide small non-coding RNAs (sncRNAs) target the mRNA of the key, innate-immune- and inflammation-related regulatory protein, complement factor-H (CFH; chr 1q32), resulting in significant decreases in CFH expression (p < 0.01, ANOVA). Our results further indicate that HNG cells respond to IL-1β + Aβ42-peptide-induced stress by significant NF-κB-modulated up-regulation of miRNA-125b- and miRNA-146a. The complex interactive signaling of NF-κB, miR-125b, miR-146a, and perhaps other miRNAs, further illustrate interplay between inducible transcription factors and multiple pro-inflammatory sncRNAs that regulate CFH expression. The novel concept of miRNA actions involving mRNA target convergence and divergence are proposed and discussed. The combinatorial use of NF-кB inhibitors with anti-miRNAs (AMs; antagomirs) may have potential against CFH-driven pathogenic signaling in neurodegenerative disease, and may redirect our therapeutic perspectives to novel treatment strategies that have not yet been considered.

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Acknowledgments

These studies were presented in part at the 11th annual Alzheimer’s Association International Conference on Alzheimer’s disease (AAICAD 11) conference in Versailles, France, 16–20 July 2011; thanks are extended to the families, physicians, and researchers who contributed to the murine and human brain bank tissue and total RNA resources used in these studies and especially to Drs. R. I. Carp, C. Chen, S. Gettner, E. Head, W. Poon, T. Saing, and Jian Zhang at donor institutions. Thanks are also extended to S. Bhattacharjee, B.M. Jones, K.P Pfefferle, and D. Guillot for expert technical assistance. Some of the brain tissues used in this study was provided by the Institute for Memory Impairments and Neurological Disorders and the University of California at Irvine Alzheimer’s Disease Research Center (UCI-ADRC); funding for the UCI-ADRC was provided by NIH/NIA grant P50 AG16573. Research on the structure and function of NF-кB and miR expression in the Lukiw laboratory were supported through Translational Research Initiative (TRI) Grants from LSU Health Sciences Center New Orleans (WJL), an Alzheimer Association Investigator-Initiated Research Grant IIRG-09-131729 (WJL), and NIH NIA grants AG18031 and AG038834 (WJL). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Aging or the National Institutes of Health.

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  1. LSU Neuroscience Center, Louisiana State University Health Sciences Center, 2020 Gravier Street, New Orleans, LA, 7011-2272, USA

    Walter J. Lukiw

  2. Russian Academy of Medical Sciences, Moscow, 113152, Russia

    Peter N. Alexandrov

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  1. Walter J. Lukiw
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  2. Peter N. Alexandrov
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Correspondence to Walter J. Lukiw.

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Lukiw, W.J., Alexandrov, P.N. Regulation of Complement Factor H (CFH) by Multiple miRNAs in Alzheimer’s Disease (AD) Brain. Mol Neurobiol 46, 11–19 (2012). https://doi.org/10.1007/s12035-012-8234-4

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  • DOI: https://doi.org/10.1007/s12035-012-8234-4

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