MicroRNA-125b (miRNA-125b) regulation of 15-lipoxygenase (15-LOX) expression and the generation of NPD1 from DHA: a potential contributor to the pathogenesis of Alzheimer’s disease (AD)

In the human central nervous system (CNS), plasma membranes are normally enriched in docosahexaenoic acid (DHA). Membrane bound DHA is liberated by phospholipase A2 (PLA2), that is subsequently converted into a 10,17S-docosatriene known as neuroprotectin D1 (NPD1). The DHA-to-NPD1 conversion appears to occur via the actions of 15-lipoxygenase (15-LOX). In the hippocampal CA1 region of Alzheimer’s disease (AD) we observe significant up-regulation in the activity of several phospolipases, including cytosolic phospholipase A2 (cPLA2), and significant deficits in the abundance of both 15-LOX and NPD1. Expression of 15-LOX appears to be regulated epigenetically and post-transcriptionally by the actions of a brain enriched, NFkB-regulated miRNA-125b which binds to the 3’-untranslated region (3’-UTR) of 15-LOX mRNA, and down-regulates 15- LOX expression. 15-LOX down-regulation, and a deficiency in neurotrophic NPD1 may be explained by the actions of a single NF-kB-up-regulated miRNA-125b, part of a mis-regulated family of inducible, NF-kB-sensitive miRNAs in AD brain. The actions of a pathologically up-regulated miRNA-125b, and other pathogenic miRNAs, may be neutralized using anti-NF-kB and/ or anti-miRNA-125b strategies, thereby returning 15-LOX and NPD1 expression back to homeostatic levels.