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Regulation of Neurotropic Signaling by the Inducible, NF-kB-Sensitive miRNA-125b in Alzheimer's Disease (AD) and in Primary Human Neuronal-Glial (HNG) Cells

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Abstract

Inducible microRNAs (miRNAs) perform critical regulatory roles in central nervous system (CNS) development, aging, health, and disease. Using miRNA arrays, RNA sequencing, enhanced Northern dot blot hybridization technologies, Western immunoblot, and bioinformatics analysis, we have studied miRNA abundance and complexity in Alzheimer's disease (AD) brain tissues compared to age-matched controls. In both short post-mortem AD and in stressed primary human neuronal-glial (HNG) cells, we observe a consistent up-regulation of several brain-enriched miRNAs that are under transcriptional control by the pro-inflammatory transcription factor NF-kB. These include miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a, and miRNA-155. Of the inducible miRNAs in this subfamily, miRNA-125b is among the most abundant and significantly induced miRNA species in human brain cells and tissues. Bioinformatics analysis indicated that an up-regulated miRNA-125b could potentially target the 3’untranslated region (3’-UTR) of the messenger RNA (mRNA) encoding (a) a 15-lipoxygenase (15-LOX; ALOX15; chr 17p13.3), utilized in the conversion of docosahexaneoic acid into neuroprotectin D1 (NPD1), and (b) the vitamin D3 receptor (VDR; VD3R; chr12q13.11) of the nuclear hormone receptor superfamily. 15-LOX and VDR are key neuromolecular factors essential in lipid-mediated signaling, neurotrophic support, defense against reactive oxygen and nitrogen species (reactive oxygen and nitrogen species), and neuroprotection in the CNS. Pathogenic effects appear to be mediated via specific interaction of miRNA-125b with the 3'-UTR region of the 15-LOX and VDR messenger RNAs (mRNAs). In AD hippocampal CA1 and in stressed HNG cells, 15-LOX and VDR down-regulation and a deficiency in neurotrophic support may therefore be explained by the actions of a single inducible, pro-inflammatory miRNA-125b. We will review the recent data on the pathogenic actions of this up-regulated miRNA-125b in AD and discuss potential therapeutic approaches using either anti-NF-kB or anti-miRNA-125b strategies. These may be of clinical relevance in the restoration of 15-LOX and VDR expression back to control levels and the re-establishment of homeostatic neurotrophic signaling in the CNS.

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Acknowledgments

This work was originally presented at the joint meeting of the ISN-ASN in the Satellite Symposium entitled “Unveiling the Significance of Lipid Signaling in Neurodegeneration and Neuroprotection” on 17–19 April 2013, Cancun, Mexico, and at the Alzheimer Association International Conference 2013 (AAIC 2013), Boston, MA, USA on 13–18 July 2013. Sincere thanks are extended to E. Head, M. Ball, W. Poon, F. Culicchia, C. Eicken, and C. Hebel for short post-mortem interval (PMI) human brain tissues or extracts, miRNA array work and initial data interpretation, and to D Guillot and AI Pogue for expert technical assistance. Thanks are also extended to the many physicians and neuropathologists who have provided high-quality, short PMI human brain tissues for study; additional human temporal lobe and hippocampal CA1 control and AD brain tissues were provided by the Memory Impairments and Neurological Disorders (MIND) Institute and the University of California, Irvine Alzheimer's Disease Research Center (UCI-ADRC; NIA P50 AG16573). The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Research in the Lukiw laboratory involving small non-coding RNA (sncRNA), miRNA, the innate immune response, amyloidogenesis and neuro-inflammation in AD, prion disease and AMD was supported through a COBRE III Project, a Translational Research Initiative Grant (LSUHSC), the Louisiana Biotechnology Research Network (LBRN), an Alzheimer Association Investigator-Initiated Research Grant IIRG-09-131729, and NIH NIA Grants AG18031 and AG038834.

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Authors and Affiliations

  1. LSU Neuroscience Center, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA

    Yuhai Zhao, Surjyadipta Bhattacharjee, Brandon M. Jones & Walter J. Lukiw

  2. Department of Ophthalmology, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA

    Jim Hill & Walter J. Lukiw

  3. Department of Microbiology, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA

    Jim Hill

  4. Department of Health Information Management, Louisiana State University, Ruston, LA, 71272, USA

    Prerna Dua

  5. Department of Neurology, Louisiana State University Health Sciences Center, New Orleans, LA, 70112, USA

    Walter J. Lukiw

  6. LSU Neuroscience Center, 2020 Gravier Street, Suite 904, New Orleans, LA, 70112, USA

    Walter J. Lukiw

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  1. Yuhai Zhao
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Zhao, Y., Bhattacharjee, S., Jones, B.M. et al. Regulation of Neurotropic Signaling by the Inducible, NF-kB-Sensitive miRNA-125b in Alzheimer's Disease (AD) and in Primary Human Neuronal-Glial (HNG) Cells. Mol Neurobiol 50, 97–106 (2014). https://doi.org/10.1007/s12035-013-8595-3

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