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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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Highly simplified schematic of an AD-relevant microRNA-messenger RNA (miRNA-mRNA) regulatory network involving 3 different miRNAs and 4 different mRNAs; this drawing graphically illustrates the molecular-genetic mechanism of microRNA (miRNA) generation and targeted miRNA-mRNA interaction; selective pathogenic families of miRNAs (for example miRNA-9, miRNA-146a and miRNA-155), transcribed from genes located on 3 different chromosomes (chr 1q22, chr 5q33.3, chr 21q21.3) generate precursor miRNAs (pre-miRNAs) which are subsequently processed into neurologically active mature miRNAs (miRNA-9, miRNA-146a and miRNA-155 shown as an example); many more chromosomes, miRNAs and mRNAs and miRNA-mRNA signaling networks are probably involved; many AD-relevant miRNA encoding genes are under transcriptional control by the pro-inflammatory transcription factor NF-kB (p50/p65); mature miRNAs subsequently find their target mRNAs (TREM2, CFH, IRAK-1, and TSPAN12 shown) and the miRNA-mRNA double-stranded RNA complex is blocked at the entrance to the ribosome (blue spherical complex on mRNA stand) and the miRNA-mRNA complex is degraded; the major mode of miRNA action in the mammalian brain is pathologically up-regulated miRNAs driving the down-regulation of AD-relevant genes (see text); single miRNAs can target multiple mRNAs and multiple miRNAs can target a single mRNA (see also Figure 3); miRNAs have established roles in recognizing multiple mRNA sequences (genetic pleiotropy), combinatorial and cooperativity in gene regulation, template accessibility (mediated by various RNA binding proteins; in this diagram orange spheres at the miRNA-mRNA interface called “Argonaute proteins”) and post-transcriptional regulation of the transcriptome (Hobert, 2008; Jaber et al., 2019; Eisen et al., 2020; Lukiw, 2020a,b). Combined with other metrics, the precise quantitation of miRNA abundance, speciation and complexity in various AD biofluids has strong potential for increasing the accuracy of AD diagnostics; recent preliminary in vitro studies further indicate that anti-miRNA (antimiR, antagomir, AM)-based therapies may be effective in quenching the excessive miRNA-mediated downregulation of critical mRNA-driven gene expression in AD (Zhao et al., 2016a,b; Jaber et al., 2019; Fan et al., 2020; Ghaffari et al., 2020).