microRNA-146a Signaling in Alzheimer's Disease (AD) and Prion Disease (PrD)

Abstract

The mouse-and human-brain-resident, nuclear factor kappa B (NF-κB)-regulated, micro RNA-146a-5p (miRNA-146a-5p) is an inducible, 22-nucleotide, single-stranded non-coding RNA (sncRNA) easily detected in several brain and immunological cell types, and an important epigenetic modulator of inflammatory signaling and the innate-immune response in several neurological disorders. Among all studied microRNAs, miRNA-146a-5p (typically referred to as just miRNA-146a) has been well characterized and its pathological function in progressive, age-related, and lethal human inflammatory neurodegenerative disease states is well documented. This communication will review our current understanding of miRNA-146a, its induction by the NF-kBstimulating actions of inflammatory mediators, including the secretory products of certain microbial species such as viral vectors, and Gram-negative bacteria (such as Bacteroides fragilis) that are normal residents of the human gastrointestinal (GI) tract microbiome, and how miRNA-146a appears to contribute to neuro-pathological, neuro-inflammatory, and altered neuro-immunological aspects of both Alzheimer's disease (AD) and prion disease (PrD).

Vesicular Transport of Encapsulated microRNA between Glial and Neuronal Cells

“…Several important unanswered questions remain in our understanding of the generation and characterization of intraluminal vesicles (ILV), microparticles (MP), exosomes (EX) and extracellular microvesicles (EMV), the nature of their vesicular cargoes and miRNA composition. These include: (i) the signals and pathways essential for stimulation and the origin of their formation, as well as the mechanism of their release from many different cell types in the CNS and their proficiency for modulating functions of target cells; (ii) the molecular-genetic injury and/or environmental factors which stimulate their release for this evolutionarily-conserved type of information communication system amongst astrocytes, microglia and neurons; (iii) their increased production and release during the initiation and spread of progressive age-related inflammatory neurodegeneration; (iv) the actual molecular contents, stoichiometry and packaging of the contents in the vesicles themselves; (v) the magnitude and signaling impact of their plasma membrane-packaged vesicular cargo; (vi) the regulation of their trafficking and targeting to neuronal cells via plasma membrane-mediated cell-surface reception mechanisms; (vii) the lipidomic, proteomic and transcriptomic profiles of these vesicles and what miRNA and/or mRNA encoded information these vesicles may be carrying; (viii) whether or not EXs and/or EMVs can transfer their miRNA-enriched intraluminal cargoes to other cell types and/or to other species; (ix) the role of circular RNA (circRNA) which have been shown in some cases to act as natural “anti-miRNA sponges ” of specific miRNA activities (Lukiw 2013 [ 77 ]; Zhao et al, 2016 [ 78 ]; Fakhoury 2018 [ 53 ]; Pogue and Lukiw., 2018 [ 33 ]; Zhao and Lukiw, 2018 [ 59 ]; Avsar et al, 2020 [ 35 ]; Groot and Lee 2020 [ 69 ]; Hou et al, 2020 [ 37 ]; Li et al, 2020 [ 19 ]; Ma et al, 2020 [ 79 ]; Serpente et al, 2020 [ 11 ]). A single microvesicle, for example, may carry a cargo consisting of a complex cocktail of multiple proteins, proteolipids, cytokines, chemokines, carbohydrates, miRNAs, mRNAs, circRNAs and/or other nucleic acid signals as well as neurotrophic and amyloidogenic factors together representing novel, unique and discrete “ information packets ” for the structural and functional support of target cells, and acting as unique mediators of intercellular information transfer.…”

Biomarkers for Alzheimer’s Disease (AD) and the Application of Precision Medicine

“…These have been found in short post-mortem interval (PMI) sporadic AD brain, in transgenic animal models of AD (TgAD), in brain biopsies, and in biofluids from AD patients. Genome-wide association studies (GWAS), epigenetic evaluations, such as miRNA-mRNA linkage or association mapping for AD-relevant neurological pathways, should provide useful diagnostic approaches since it has recently become apparent that miRNA-mediated mRNA-targeted regulatory mechanisms involve a large number of pathogenic and highly integrated gene expression pathways in the CNS [ 25 , 32 , 45 , 46 , 47 , 48 ]. To cite one very recent example, the human-brain-resident, nuclear factor kappa B p50/p65 (NF-κB p50/p65)-regulated microRNA-146a (miRNA-146a) is an inducible, 22-nucleotide, single-stranded non-coding RNA (sncRNA) easily detected in CNS neurons and immunological cell types.…”

“…To cite one very recent example, the human-brain-resident, nuclear factor kappa B p50/p65 (NF-κB p50/p65)-regulated microRNA-146a (miRNA-146a) is an inducible, 22-nucleotide, single-stranded non-coding RNA (sncRNA) easily detected in CNS neurons and immunological cell types. An inducible miRNA-146a: ( i ) is significantly up-regulated in AD brain tissues, CSF, and blood serum [ 25 , 48 ]; ( ii ) is an important epigenetic modulator of inflammatory signaling and the innate-immune response in several neurological disorders; and ( iii ) is essential in the down-regulation of the innate-immune regulator complement factor H (CFH; [ 10 , 20 , 23 , 25 , 40 , 46 , 49 ]).…”

“…LPS- and NF-kB (p50/p65)-inducible microRNAs, such as miRNA-146a and miRNA-125b, appear to contribute to neuropathological, neuro-inflammatory, and altered neuro-immunological aspects of both AD and prion disease (PrD; [ 25 , 32 , 40 , 46 , 48 , 49 , 50 ]). Interestingly, NF-κB-sensitive up-regulated miRNAs and their down-regulated mRNA targets appear to constitute an integrated NF-κB-miRNA-mRNA signaling network implicated in multiple AD pathophysiological processes [ 10 , 40 , 45 , 48 , 50 , 51 ].…”

“…Hence, potential signaling pathways to the acquisition of the AD phenotype appear to occur in part via an integrated and highly complex system of multiple miRNA-mRNA interactions that define many key pathogenic and pro-inflammatory gene expression pathways. Genetic and epigenetic signaling via miRNA-mRNA networks in the brain may be one of the most useful as potential biomarkers for early AD detection as they can detect subtle failure in multiple AD-relevant brain signaling systems and metabolic pathways [ 10 , 25 , 45 , 49 , 51 ].…”