Figure 1.

Schematic diagram illustrating pathogenic signaling circuits in sporadic AD brain and potential therapeutic strategies for intervention. Recent observations suggest the presence of a cyclical and self-reinforcing pathogenic “AD relevant stressor(s)-NF-kB- miRNA-mRNA-gene expression loop” in AD brain; this signaling pathway may be amenable to anti-miRNA (AM) and/or NF-kB inhibitor therapeutic strategies that in theory should help restore homeostatic gene expression to the damaged brain. Sporadic AD relevant stressors include age, diet (such as high fat-cholesterol intake), environmental, lifestyle, exposure to viruses (such as HCV or HSV-1), environmental toxins (such as aluminum), epilepsy, prions, and other neurological diseases and other factors; each of these AD-relevant stressors are known induce NF-kB signaling (Lukiw et al., 2008; Cui et al., 2010; Lukiw, 2012a,b, 2013a; Hill et al., 2015b; Srinivasan and Lahiri, 2015; Yuan et al., 2015); NF-kB signaling has been observed to be generally up-regulated in AD brain that subsequently up-regulates the transcription from NF-kB sensitive pro-inflammatory miRNA promoters (Lukiw and Bazan, 1998; Lukiw et al., 2008; Cui et al., 2010; Devier et al., 2015; Kaur et al., 2015; Srinivasan and Lahiri, 2015); in turn up-regulated miRNAs generally down-regulate their mRNA targets; for example miRNA-146a, a well characterized pro-inflammatory miRNA contains three active canonical NF-kB recognition features in its promoter (Lukiw et al., 2008; Cui et al., 2010); up-regulated miRNAs may pathologically down-regulate a family of AD relevant mRNAs that are involved in synaptogenesis, neurotrophism, the innate-immune response, inflammation and amyloidogenesis (Loring et al., 2001; Cogswell et al., 2008; Kaur et al., 2015; Srinivasan and Lahiri, 2015). It has been possible, for example, to throttle-up or throttle down miRNA-146a expression in AD primary brain cell culture models using AD-relevant inducers or combinations of AM ribonucleotide sequences and NF-kB inhibitors (Lukiw et al., 2008; Cui et al., 2010; Lukiw, 2012a, 2013a). AD-relevant stressors and NF-kB may also directly induce pro-inflammatory mRNAs that possess NF-kB binding sites in their immediate promoters. While it may be difficult to reduce lifelong exposure to AD relevant stressors it may be possible (i) to specifically inhibit miRNA up-regulation using anti-miRNA (AM) ribonucleotide sequences 100% complementary to up-regulated brain miRNAs, and/or (ii) to directly inhibit NF-kB up-regulation (several hundred NF-kB inhibitors are known). The intrinsic problem with excessive NF-kB inhibition is that many homeostatic cell processes rely on NF-kB signaling so the potential for unwanted off-target effects using NF-kB inhibitors may be both severe and numerous (Lukiw, 2012a,b, 2013a; Yuan et al., 2015). The actions of miRNA signaling may in turn modulate NF-kB signaling. Overall, it may be a better strategy to inhibit miRNAs using highly specific and selective AM sequences to target just a single or a few miRNA-mRNA-mediated signaling pathways, particularly those which are the most significantly up-regulated in AD brain. The combinatorial use of AM strategies and NF-kB inhibitors may turn out to be the most effective in the clinical management of AD, and their stoichiometry may need to be carefully adjusted to meet the needs of individual AD patients (Lukiw et al., 2008; Cui et al., 2010; Lukiw, 2012a,b, 2013a; Srinivasan and Lahiri, 2015; Yuan et al., 2015). The efficient delivery of AM ribonucleotide sequences remains a challenging therapeutic problem (Janssen et al., 2013; Zhang et al., 2013; Brites and Fernandes, 2015; Kang et al., 2015; Properzi et al., 2015; van der Pol et al., 2016; Wang et al., 2015).