MicroRNA alterations in neuropathologic cognitive disorders with an emphasis on dementia: Lessons from animal models

Abstract

Cognitive dysfunction is a state of losing or having difficulties in remembering, learning, focusing, or making decisions that impact individual healthy life. Small single-stranded and nonprotein coding RNAs, microRNAs (miRNAs) participate actively in regulatory processes, incorporate cognitive signaling pathways, and intensely affect cognitive evolution. miRNAs exert their modification activities through translational or transcriptional processes. Reportedly, cognitive impairment and dementia are rising, especially in developing countries. Herein we provided a brief review of original studies addressing miRNA changes in the most common neurological diseases with a focus on dementia and Alzheimer's disease. It must be How to cite this article: Bahlakeh G, Gorji A, Soltani H, Ghadiri T. MicroRNA alterations in neuropathologic cognitive disorders with an emphasis on dementia: Lessons from animal models.

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).…”

“…The multi-system, multi-pathway and sometimes overlapping regulatory roles for potentially pathogenic miRNA gene families in the neocortex, hippocampus, the limbic system and the CNS in general make miRNA prime candidates for modulating the expression of many mRNA targets in complex, progressive and ultimately lethal neurological disorders of the CNS that include AD (Lukiw, 2007;Zhao et al, 2016a,b;Jaber et al, 2017Jaber et al, , 2019; Figure 2). It is for this reason there has been much recent interest in vesicle-encapsulated and/or biofluid-enriched monomeric miRNAs as potential ribonucleic acid indicators which are predictive and/or diagnostic biomarkers for the onset and development of AD (Bahlakeh et al, 2020;Krammes et al, 2020;Serpente 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).…”

MiRNA-15b and miRNA-125b are associated with regional Aβ-PET and FDG-PET uptake in cognitively normal individuals with subjective memory complaints

“…Experimental models of aging and Alzheimer's disease (AD), as well as in-human post-mortem and in vivo biomarker-based studies, indicate that the dysregulation of several miRNAs may influence AD pathophysiological mechanisms, including the amyloid-β (Aβ) pathway, tau pathology, brain immune, and inflammatory response, oxidative stress regulation, among others [7][8][9][10][11][12][13][14][15][16] .…”

“…Emerging data encourage further analysis and characterization of specific miRNAs that may be either downregulated or upregulated aberrantly in the prodromal and preclinical phases of AD 7,8,[14][15][16] , where treatments with putative disease-modifying effect are more likely to be effective [17][18][19] .…”

Expression of tiRNA and tRF in APP/PS1 transgenic mice and the change of related proteins expression

“…With the development of revolutionary deep sequencing technologies, some small ncRNAs (sncRNAs), such as small interfering RNA (siRNA), microRNA (miRNA), and piwiinteracting RNAs (piRNAs) have been shown to regulate diseases such as AD, cancer, and some others (10)(11)(12)(13). The miRNAs and piRNAs could regulate some pathological processes of AD, such as regulation of secretases, APP and Tau expression (12), and could affect cognitive evolution (13). In recent years, another sncRNA was discovered and slowly gained recognition, that is transfer RNA (tRNA)-derived fragments (tiRNA and tRFs) which are the fragments cleaved at specific sites of tRNA.…”