Exosomal microRNAs as diagnostic biomarkers and therapeutic applications in neurodegenerative diseases

Comparative Insight into Microglia/Macrophages-Associated Pathways in Glioblastoma and Alzheimer’s Disease

“…This unique characteristic position miRNA as a viable candidate for biomarkers and biosensors, potentially revolutionizing the diagnosis and prognosis of disease development and progression. Since 2008, miRNA has been established as a biomarker for diffuse large B-cell lymphoma through patented serum [ 101 ], used to diagnose a variety of cancers [ 102 , 103 ], and its use in neurodegenerative diseases, including AD, has begun to be explored [ 104 , 105 ]. For GBM studies, our recent work demonstrates the successful classification and detection of GBM BVZ-responsive subtypes using a combination of three miRNA expressions alongside AI analysis techniques, laying a foundation for personalized medicine approaches in GBM treatment [ 106 ].…”

MicroRNA (miRNA) Complexity in Alzheimer’s Disease (AD)

“…The following selective points are applicable to our current understanding of miRNA abundance, speciation, complexity and trafficking in the AD-affected brain and CNS compared to age- and gender-matched controls: Multiple independent studies using Northern analysis with single or multiple radiolabeled or fluorescent probes, RNA sequencing and/or DNA, mRNA and/or miRNA array technologies indicate that gene expression as indexed by total messenger RNA (mRNA) abundance and yield is in general reduced in AD brains, probably a reflection of aging brain cells ‘shutting down’, and this correlates with a resultant inability to meet homeostatic demands and/or related molecular-genetic mechanisms in which total mRNA populations are found to be significantly reduced [ 45 , 47 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 ]; As mammalian miRNAs predominantly act to decrease target mRNA levels, down-regulated gene expression indicates that down-regulated mRNA is, in part, probably the consequence of up-regulated miRNA as is widely observed in AD-affected brain tissues [ 34 , 35 , 48 , 49 , 52 , 73 ]; interestingly, many of the up-regulated miRNAs in AD are inducible and under transcriptional control of the pro-inflammatory transcription factor NF-kB (p50/p65) complex [ 29 , 30 , 35 , 52 , 73 ]; clearly, other inducible miRNAs and/or ROS and pro-inflammatory transcription factors may be involved; Importantly, no de novo appearance of any novel miRNAs has ever been observed in AD affected brains, only the up-regulation of existing miRNAs already present, and normally at homeostatic levels in age- and gender-matched control brain samples; Several independent studies have quantified and implicated the same brain-enriched miRNA species in the molecular-genetic processes involving innate-immune disruption, synaptic signaling deficits and inflammatory neurodegeneration as is observed in AD brains and verified in human brain cells, transgenic AD (TgAD) and other neurodegenerative disease models; these include at least 31 miRNAs all found to be significantly dysregulated in AD brains compared to age- and gender-matched controls from the same anatomical region; most appear to be up-regulated in mean relative abundance in anatomically-specific brain regions [ 5 , 6 , …”

“…Multiple independent studies using Northern analysis with single or multiple radiolabeled or fluorescent probes, RNA sequencing and/or DNA, mRNA and/or miRNA array technologies indicate that gene expression as indexed by total messenger RNA (mRNA) abundance and yield is in general reduced in AD brains, probably a reflection of aging brain cells ‘shutting down’, and this correlates with a resultant inability to meet homeostatic demands and/or related molecular-genetic mechanisms in which total mRNA populations are found to be significantly reduced [ 45 , 47 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 ];…”

“…One of the most-studied NF-kB (p50/p65)-induced and up-regulated miRNAs in AD brain neocortex and hippocampus is the 22 nt ssRNA pro-inflammatory and neuroimmune regulator miRNA-146a-5p (miRNA-146a) [ 30 , 35 , 36 , 37 , 39 , 41 , 48 , 49 , 77 ]; miRNA-146a, normally a brain- and CNS-abundant ssRNA, has been found to be significantly up-regulated in progressive and terminal viral- and prion disease (PrD)-mediated neurological disorders and in related neurological syndromes associated with inflammatory neurodegeneration, including at least eighteen different viral-induced encephalopathies for which data are available, in at least ten known PrDs of animals and humans, AD and in other sporadic and progressive age-related neurological diseases [ 36 , 37 , 39 , 40 , 41 , 49 , 77 , 92 ]. Despite the apparent absence of nucleic acids in prions, both DNA- and RNA-containing viruses (along with prions) significantly induce miRNA-146a in the infected host; however, whether this represents part of the host’s adaptive immunity, innate-immune response or a mechanism to enable the prion or virus a successful invasion of the host is still not well understood [ 30 , 37 , 38 , 39 , 41 , 91 ];…”

“…Very recent evidence suggests that miRNA translocation and trafficking in AD brains may in part be mediated by a network of lymph- and blood-borne nanovesicles (NV), exosomes (EXs) and/or extracellular microvesicles (EMVs) throughout highly vascularized brain tissues; NVs, EXs and EMVs are representative of a diverse collection of plasma membrane-derived nanovesicles, 30–1000 nm in diameter, released by all cell lineages of the human CNS; these nanovesicles are examples of a very active and dynamic form of extracellular communication and the conveyance of biological information transfer essential to maintain homeostatic neurological function; NVs, EXs and EMVs contain complex molecular cargoes that are representative of the cytoplasm of their cells of origin [ 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 ]; these include various mixtures of lipids, glycolipids, cytokines, chemokines, proteins, proteolipids, carbohydrates, polysaccharides, miRNAs, mRNAs, inflammatory mediators and other components, including end-stage neurotoxic and pathogenic metabolic products, such as tau fragments, lipopolysaccharide (LPS) and various amyloid beta (Aβ) peptides [ 91 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 ];…”