Antagonism of NF-κB-up-regulated micro RNAs (miRNAs) in sporadic Alzheimer's disease (AD)—anti-NF-κB vs. anti-miRNA strategies

Abstract

As research into micro RNA (miRNA) speciation, complexity, and biological activity progresses, it is becoming clear that a selective subset of all so far characterized miRNAs utilized by human cells and tissues is under the transcriptional control of the pro-inflammatory and immune system-linked transcription factor NF-κB (Sen and Baltimore, 1986; Lukiw and Bazan, 1998; Taganov et al., 2006; Lukiw, 2007, 2012a,b,c; Bazzoni et al., 2009; Ma et al., 2011; Boldin and Baltimore, 2012; Cremer et al., 2012; Li et al., 2012; Lukiw and Alexandrov, 2012; Zhao et al., 2013). The inducible up-regulation of NF-κ B-sensitive miRNAs is by virtue of single, and often multiple, NF-κB-DNA binding recognition sites in the regulatory regions of miRNA-containing genes that drive RNA polymerase II-mediated transcription of pre-miRNA species (Ambros, 2004; Taganov et al., 2006; Baltimore et al., 2008; Cui et al., 2010; Guo et al., 2010; Bredy et al., 2011; Lukiw, 2012a). In neurodegenerative disease research, stress-triggered up-regulation of these NF-κ B-induced miRNAs appear to be playing pathogenic roles in the down-regulation of brain-essential messenger RNAs (mRNA), and the initiation and propagation of pathological gene expression programs that are, for example, characteristic of the Alzheimer's disease (AD) process (Figure ​(Figure1).1). NF-κB-mediated up-regulated miRNAs and down-regulated mRNA targets thereby form a highly integrated, pathogenic NF-κ B-miRNA-mRNA signaling network that can explain much of the observed neuropathology in AD, including deficits in phagocytosis (Niemitz, 2012; Zhao et al., 2013), NF-κ B-mediated innate-immune signaling and chronic inflammation (Cui et al., 2010; Heneka et al., 2010; Lukiw and Bazan, 2010; Lukiw et al., 2012), impairments in neurotransmitter packaging and release, neurotrophism and amyloidogenesis (Xu et al., 2009; Lukiw, 2012a,b,c). Under homeostatic conditions, NF-κ B activation involves a coordinated, sequential, and self-limiting sequence of events controlled by positive and negative regulatory mechanisms, however, this does not appear to be the case in early, moderate or especially advanced stages of sporadic AD. In sporadic AD, once initiated, NF-κ B-mediated disruption of homeostatic gene expression can be self-perpetuating due, in part, to the chronic re-activation of NF-κ B activities via up-regulation of interleukin-1β receptor associated kinase-2 (IRAK-2) signaling pathways (Cui et al., 2010). Selective inhibition of the actions of NF-κ B and specific NF-κ B-sensitive miRNAs therefore seems a plausible therapeutic strategy towards neutralizing their combined effects in sporadic AD, and related progressive, age-related neurological diseases with an innate-immune and inflammatory component.