Recent Advances in the Roles of MicroRNA and MicroRNA-Based Diagnosis in Neurodegenerative Diseases

Abstract

Neurodegenerative diseases manifest as progressive loss of neuronal structures and their myelin sheaths and lead to substantial morbidity and mortality, especially in the elderly. Despite extensive research, there are few effective treatment options for the diseases. MicroRNAs have been shown to be involved in the developmental processes of the central nervous system. Mounting evidence suggest they play an important role in the development of neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. However, there are few reviews regarding the roles of miRNAs in neurodegenerative diseases. This review summarizes the recent developments in the roles of microRNAs in neurodegenerative diseases and presents the application of microRNA-based methods in the early diagnosis of these diseases.

Endogenous miRNA-Based Innate-Immunity against SARS-CoV-2 Invasion of the Brain

“…This may be especially important in susceptible COVID-19 patients, and especially in the elderly and people who have survived more serious episodes of COVID-19 infection [ 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 ]. Interestingly, for the limited research that has already been undertaken, certain natural miRNAs such as the NF-kB (p50/p65)-inducible hsa-miRNA-146a-5p are significantly induced in host cells in response to viral invasion, but whether this is part of a successful invasion strategy for the virus or part of a neuroprotective mechanism is still not well understood [ 17 , 18 , 19 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ]. In fact, miRNA-146a-5p is significantly over-expressed in progressive and often lethal viral- and prion-mediated and related neurological syndromes associated with progressive inflammatory neurodegeneration, including at least ~18 different viral-induced encephalopathies, such as SARS-CoV-2, and for which data are currently available [ 16 , 41 , 49 , 50 , 51 ].…”

“…The widely observed variance in miRNA abundance, speciation, and complexity in normal, healthy aging in individuals defines in part what particular miRNA species are present, and specific patterns of miRNA abundance appear to have an impact on the particular physiological or pathophysiological status of individual susceptibility to both viral invasion and progressive inflammatory neurodegeneration [ 29 , 30 , 41 ]. Interestingly, a defined set of overexpressed miRNAs has been associated with an increased risk for the development of AD; therefore, it is reasonable to suggest that a specific set of host miRNAs and their specific cellular abundance may also confer susceptibility to, or protection against, ssRNA-based infectivity, viral-based infectious disease, and/or other forms of age-related inflammatory neurodegeneration [ 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 ].…”

“… Legend to Table 1 : Age Range (years) = age range of control tissues used in these studies (in years); Mean Age = average age of all superior temporal lobe neocortical tissue samples (STLN; Brodmann Area 22) in years plus or minus one standard deviation (SD); PMI = post-mortem interval (death to brain freezing interval at −81 °C); range in hours; numbers in the ‘total RNA quality’ column are indices for RNA spectral purity and represent the ratio of spectral absorbance of RNA scanned at 260 nm/280 nm, based on a total N = 27; the use of RNase-free plastic-ware and extraction reagents containing RNAsecure (Ambion-Invitrogen; ThermoFisher Scientific Inc., Waltham, MA, USA) ribonuclease inhibitors and short PMI brain tissues of the highest qualities obtainable yielded high-spectral quality total RNA, as analyzed using RNA LabChip Analysis Chips (Caliper Life Sciences Inc.-PerkinElmer, Waltham MA, USA;) and a 2100 Bioanalyzer (Agilent Technologies; Santa Clara, CA, USA) [ 68 , 69 ]; miRNA fractions were obtained from total STLN RNA using selective small RNA extraction and an miRNeasy Micro Kit [ 50 ] (Cat.No./ID: 217084; Qiagen, Germantown, MD, USA) and were analyzed on miRNA analytical arrays (proprietary MRA-1001-miRNA microfluidic chip analytical platform (LC Sciences Corporation, Houston, TX, USA; (accessed on 26 December 2022); data derived from [ 50 , 51 , 55 , 58 , 61 , 65 , 66 , 67 , 68 , 69 ]; see below and Table 2 ). …”

“… Legend to Table 2 : This table indicates the most abundant unique miRNAs detected in the human brain superior temporal lobe neocortex (STLN; Brodmann Area 22); abundances are ranked by miRNA numerical designation, based on pooled data from N = 27 short post-mortem interval (PMI) control tissues; data derived from [ 50 , 51 , 55 , 58 , 61 , 65 , 66 , 67 , 68 , 69 ]; this group included 9 males and 18 females, mean age 75.2 ± 9.5 years; all post-mortem intervals (PMIs; death to brain freezing at −81 °C) were less than 3.3 h (see Table 1 ); each of these miRNAs yielded high (≥3000) units of signal strength on LC Sciences miRNA analytical arrays Genechip (proprietary MRA-1001-miRNA microfluidic chip analytical platform; 2650 small non-coding RNAs (sncRNAs) were analyzed; LC Sciences Corporation, Houston, TX, USA; on 26 December 2022) and ranked as the 54 most abundant miRNAs detected in the superior temporal lobe neocortex; except for miRNAs listed here, all other miRNAs are at a significantly lower abundance; note that there is a relatively high basal abundance of the let-7a to let-7i group of miRNAs; also note that AD-abundant miRNAs such as miRNA-9, miRNA-30b, miRNA-34a, miRNA-125b, miRNA-146a, and miRNA-155 exhibit high relative variability in mean abundance in control brains and are significantly up-regulated in AD brains; in human neuronal-glial (HNG) cells in primary culture, most of these same miRNAs are induced by the pro-inflammatory transcription factor NF-kB (p50/p65) [ 66 ]; these same miRNAs are up-regulated in AD brains, especially as AD progresses; superior temporal lobe-enriched miRNAs overlain in gray (and their mRNA targets) have been strongly implicated in AD [ 23 , 50 , 51 , 52 , 53 , 54 , 55 , 57 , 66 ]; miRNAs with a single asterisk such as miRNA-7, miRNA-9, miRNA-30b, miRNA-34a, miRNA-125b, and miRNA-146a are moderately abundant in control of the adult human superior temporal lobe neocortex (Brodmann Area 22); many of these same miRNAs are implicated in other infectious, inflammatory, and/or immunological diseases [ 11 , 12 , 23 , 24 , 25 , 26 , 27...…”

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

“… Complex integration of miRNA–mRNA signaling in AD brain hippocampus. Legend to Figure 1 : This highly schematized figure indicates how the up-regulation of just eight miRNAs (central gray boxes; small black arrows pointing upward within the box) impacts the levels for 13 AD-relevant mRNAs (green boxes; small black arrows pointing downward within box) and can explain much of the neuropathology of AD; all eight miRNAs are under NF-kB regulatory control and all have been reported to be upregulated in AD brain tissues [ 29 , 30 , 31 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ] ( Table 2 ); all eight up-regulated miRNAs are highlighted in gray in Table 2 ; all long red arrows are established interactions; long black arrows represent predicted interaction(s); miRNAs predominantly act to decrease mRNA levels and different miRNAs may have multiple mRNA targets [ 8 , 10 , 11 , 12 , 15 , 25 , 34 , 51 , 52 , 53 ]; other miRNA-mRNA pairings may be involved; interestingly both miRNA-146a and miRNA-155 upregulation lead to a down-regulation of IRAK-1 expression with a compensatory surge in the expression of IRAK-2 that leads to altered NF-kB signaling and inflammation [ 48 ]; abbreviations: TSPAN7,12 = tetraspanin transmembrane proteins 7 and 12 [ 24 ]; SHANK3 = SH3 and multiple ankyrin repeat domain protein 3 [ 53 ]; CFH = complement factor H [ 7 , 12 , 17 , 35 ]; IRAK 1,2 = interleukin-1 receptor-associated kinase-1 [ 48 ]; UBE2A = ubiquitin conjugating enzyme 2A [ 54 ]; NFL = neurofilament light chain (involved in neuronal shape and cytoarchitecture) [ 55 ]; IkBKG = inhibitor of the nuclear factor kappa B kinase regulatory subunit gamma [ 29 , …”