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

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-κBsensitive 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, stresstriggered up-regulation of these NF-κBinduced 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 1). NF-κB-mediated up-regulated miRNAs and down-regulated mRNA targets thereby form a highly integrated, pathogenic NF-κB-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-κB-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-κB 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-κB-mediated disruption of homeostatic gene expression can be self-perpetuating due, in part, to the chronic re-activation of NF-κB 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-κB and specific NF-κB-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. The brain-ubiquitous transcription factor NF-κB comprises a family of heterodimeric DNA-binding proteins, for example the relatively common p50–p65 complex, that normally reside in a “resting state” in the cytoplasm (Sen and Baltimore, 1986; Lukiw and Bazan, 1998; Mattson and Camandola, 2001; Yamamoto and Gaynor, 2001; Lukiw, 2012a,b). In general, cytoplasmic NF-κB activation is stimulated via a wide array of physiological stressors including ionizing radiation, viral infection, neurotoxic metals, elevations in reactive oxygen species (ROS), inflammatory cytokines and chemokines, Aβ42 peptides, hypoxia, and other forms of physiological stress (Baltimore et al., 2008; Pogue et al., 2009, 2011; Boldin and Baltimore, 2012). This activation is largely mediated by the serinephosphorylation of a family of NF-κB inhibitory subunits, non-covalently bound to the NF-κB heterodimer, and collectively known as the inhibitors of kappaB (IκB). IκB phosphorylation is followed, in turn, by IκB degeneration, in part through cooperation with NF-κB essential modulator (NEMO) proteins (Baltimore et al., 2008; Shifera, 2010). NF-κB heterodimers next translocate to the nucleus to target binding sites homologous to the canonical DNA sequence 5′-GGGACTTTCC-3′ in the regulatory regions of NF-κBsensitive genes (Meffert and Baltimore, 2005; Wong et al., 2011). Ever since NF-κB’s original description in 1986 several hundred NF-κB inhibitors, both natural and synthetic, have been developed to inhibit NF-κB-activation in this complex signaling network (Sen and Baltimore, 1986; Mattson and Camandola, 2001; Aggarwal and Shishodia, 2004; Meffert and Baltimore, 2005; Gilmore and Herscovitch, 2006; Nam, 2006; Gilmore and Garbati, 2011). Indeed, inhibition of NF-κB can involve multifaceted aspects of NF-κB activation via blocking of NF-κB signaling at various control points, from inhibition of the kinases that phosphorylate IκB (thus preventing activation of NF-κB), to the deacetylation of the NF-κB