MicroRNA-146a Is a Wide-Reaching Neuroinflammatory Regulator and Potential Treatment Target in Neurological Diseases

Abstract

HIGHLIGHTS-Alterations in the microRNA-146a (miR-146a) level are common events in the pathogenesis of most neurological diseases.

microRNA-Based Biomarkers in Alzheimer’s Disease (AD)

“…Patterns of miRNA expression are complex -for example natural miRNA abundance has been shown to fluctuate during neural development and differentiation of the human brain and in the aging CNS (Giorgi Silveira et al, 2020;Ma et al, 2020;Wu and Kuo, 2020). Emerging data continue to support the concept that the analysis and characterization of specific miRNAs may be especially useful in the prodromal and pre-clinical phases of AD in which a very subtle pro-inflammatory neuropathology develops and molecular changes begin to accumulate even in the absence of the full-blown clinical symptoms as shown by the moderate and more advanced phases of AD (Hill and Lukiw, 2016;Bahlakeh et al, 2020;Fan et al, 2020;Ma et al, 2020;Wu and Kuo, 2020).…”

“…These findings support the strengthening contention: (i) that brain-enriched miRNAs operate as fundamental components of an epigenetically controlled post-transcriptional signaling network in the mammalian CNS Kleaveland et al, 2018;Jaber et al, 2019;Eisen et al, 2020); and (ii) that miRNAs have an established capability to act independently, coordinately and/or cooperatively to create a highly sophisticated and interactive regulatory miRNA-mRNA network for families of brain genes that regulate many essential brain functions that are specifically altered in AD brain (Jaber et al, 2017;Kleaveland et al, 2018;Eisen et al, 2020;Lukiw, 2020a,b). Importantly, information-carrying ribonucleic acids such as highly soluble and mobile, single-stranded non-coding RNAs (sncRNAs) including microRNAs (miRNAs) can affect the operation of a large number of highly interactive pathogenic signaling pathways in the CNS, and represent strategic candidates for promoting AD onset, and for modulating or maintaining AD propagation and disease spread (Alexandrov et al, 2012;Chandrasekaran and Bonchev, 2016;Clement et al, 2016;Kleaveland et al, 2018;Lemcke and David, 2018;Hill, 2019;Jaber et al, 2019;Konovalova et al, 2019;Condrat et al, 2020;Fan et al, 2020;Kou et al, 2020).…”

“…Indeed homeostatic FIGURE 2 | 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). levels of all 2650 miRNAs are an excellent indicator of normal brain operation and of homeostatic brain function in health and in aging, the development of dyshomeostasis, and the onset of disease.…”

“…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).…”

Vesicular Transport of Encapsulated microRNA between Glial and Neuronal Cells

“…These extruded vesicles were subsequently observed to be taken up by normal host brain microvascular endothelial cells, thereby inducing carcinogenic type phenotypic change in these brain cells, stimulating tumor invasion, proliferation and cancer spread mediated by endothelial cells of the neurovasculature (Hunter et al, 2008 [ 36 ]; Skog et al, 2008 [ 25 ]). Very recently, evidence has been provided showing that EXs and EMVs derived from miRNA-containing natural killer (NK) cells contribute to immunological surveillance and their provision of specific miRNAs may be the first-line of defense in the regulation of tumor cell growth, cytotoxicity and metastasis diffusion in the CNS (Briand et al, 2020 [ 8 ]; Federici et al, 2020 [ 62 ]). As discussed more fully below, it has recently been shown that brain EXs and EMVs released from diseased astrocytes and “activated microglia” carry specific miRNA-enriched cargoes, enriched in miRNA-34a and miRNA-125b for example, that contribute to neuropathological spreading and the exacerbation of neuropathological processes in AD, ALS, Parkinson’s disease (PD), Huntington’s disease (HD), stroke and other neuro-inflammatory degenerative conditions.…”