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.
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