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

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.