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. 2020 Oct 30;14:585432. doi: 10.3389/fnins.2020.585432

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Copyright © 2020 Zhao, Jaber, Alexandrov, Vergallo, Lista, Hampel and Lukiw.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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An example of a highly interactive miRNA-mRNA regulatory network involving 5 miRNAs and 9 mRNAs; there is a significant contribution of up-regulated miRNA signaling (red boxes) to specific aspects of the down-regulated mRNA-mediated expression of key AD-relevant genes (green boxes) and AD neuropathology (Chandrasekaran and Bonchev, 2016; Clement et al., 2016; Hill and Lukiw, 2016; Jaber et al., 2017, 2019; Lukiw, 2020a,b). Just 5 significantly up-regulated miRNAs – miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a, and miRNA-155 (all reported to be up-regulated in AD and/or TgAD models) – can account for the down-regulation of 8 mRNA targets critically involved in multiple aspects of AD neuropathology (IRAK-2 is up-regulated due to a compensatory mechanism as described in Cui et al., 2010). Briefly, these miRNAs down-regulate miRNA-directed mRNA target degradation involved in phagocytosis deficits, amyloidogenesis and tau pathology (TREM2, TSPAN12), inflammation, NF-kB- and innate-immune signaling (IkBKG, CFH, IRAK1; with a compensatory increase in IRAK-2), neurotropism (15-LOX, VDR), synaptic maintenance and synaptogenesis (SYN-2), all of which are distinguishing pathological features characteristic of AD neuropathology. Using DNA and RNA sequencing, microfluidic-based GeneChip microarray analysis and advanced LED-Northern dot blot analysis it has been recently reported that: (i) miRNA-9, miRNA-34a, miRNA-125b, miRNA-146a and miRNA-155 are easily detected in the human brain neocortex and retina; (ii) all have NF-kB-recognition features in their immediate upstream promoters; (iii) these same miRNAs are induced by increases in NF-kB due to reactive-oxygen species (ROS) induced stress; and (iv) these 5 miRNAs form a pro-inflammatory gene family up-regulated in AD brain neocortex and hippocampal CA1 (Colangelo et al., 2002; Cogswell et al., 2008; Zhao et al., 2015; Fan et al., 2020; Lukiw, 2020a,b). This diagram is based on studies from our laboratories in which each AD and age-and gender-matched control sample (N∼135) were interrogated for 2,650 human miRNAs and 27,000 human mRNAs using RNA sequencing, microarray analysis and/or advanced LED-Northern dot blotting technologies in a single experiment and miRNA-mRNA linkage analysis and bioinformatics were subsequently analyzed (Jaber et al., 2019; Fan et al., 2020; Lukiw and Pogue, 2020; manuscript in preparation).