Table 1 microRNAs in the regulation of BBB functions in different CNS disorders
CNS disorders | Year | miRNAs | miRNA levels in disease | Study materials | Main regulatory effects on BBB | Main mechanisms | Refs. |
|---|---|---|---|---|---|---|---|
Ischemic stroke | 2010 | miR-15a | Up | Mice, CECs | Downregulation of miR-15a protects BBB and reduces cerebral infarction | Upregulation of PPARϭ reduces ischemia-induced miR-15a, resulting in posttranscriptional inhibition of bcl-2 | [64] |
2015 | miR-29b | Down | Mice | miR-29b reduces infarct volume, edema, BBB disruption | miR-29b overexpression directly targets Aquaporin-4 | [53] | |
2016 | miR-34a | Up | bEnd.3 | miR-34a increases BBB permeability and disrupts ZO-1, impairs mitochondrial oxidative phosphorylation, reduces ATP production | miR-34a directly targets cytochrome c (CYC C) | [67] | |
2016 | miR-150 | Down | Rats, BMECs | miR-150 increases BBB permeability and decreases cell survival | miR-150 could directly regulate the angiopoietin receptor Tie-2 and downregulate claudin-5 expression | [70] | |
2016 | miR-122 | Down | Rats | Systematic miR-122 administration decreases neurological deficits, brain infarction and maintains BBB integrity | miR-122 mimic downregulates direct target genes (e.g., VCAM-1, iNOS, PLA2G2A) and indirect target genes (e.g., ALOX5, ITGA2b, TIMP-3, IL-1b, IL-2, MMP-8) | [71] | |
2017 | miR-210 | Up | Neonatal rats | miR-210 exacerbates cerebral edema and BBB leakage | miR-210 directly targets tight junction protein occludin and catenin | [72] | |
2018 | miR-21 | Rats | miR-21 reduces ischemic hemisphere volume, cerebral infarct volume, BBB permeability | miR-21 directly targets MAP2K3, and decreases p38, MAP2K3, iNOS, MMP-9 | [73] | ||
2018 | miR-539 | Down | Rats, BMECs | miR-539 alleviates BBB Disruption | miR-539 suppresses MMP-9 expression | [74] | |
2018 | miR-155 | Not detected | hBMECs | miR-155 inhibition improves endothelial monolayer integrity | miR-155 directly targets claudin-1, and miR-155 inhibition increases claudin-1 and ZO-1 | [75] | |
2018 | miR-149-5p | Down | Rats, mBVPs | miR-149-5p decreases pericyte migration, attenuates BBB permeability, and improves the outcomes | miR-149-5p negatively regulates S1PR2, increases N-cadherin expression and decreases pericyte migration | [77] | |
Ischemic stroke/TBI | 2019 | miR-212/132 | Up | Mice, hBMECs | miR-212/132 overexpression decreases barrier properties and reduces EC migration | miR-212/132 overexpression decreases claudin-1, JAM3, and TJAP1 | [222] |
Ischemic stroke | 2019 | miR-1 | Up | Rats | miR-1 inhibition improves neurological deficits, reduces infarction volume, brain edema, and BBB permeability | N/A | [78] |
2019 | miR-132 | Down | Rats | miR-132 decreases the infarct volume, reduces brain edema, preserves the integrity of BBB, and improves neurological functions | miR-132 suppresses MMP-9 mRNA and decreases the degradation of tight junction proteins VE-cadherin and β-Catenin | [79] | |
2019 | miR-34a | Up | Mice, CECs | miR-34a disrupts ZO-1 and induces BBB permeability | miR-34a reduces the expression of CYC C | [68] | |
2020 | miR-15a/16–1 | Up | Mice, mBMECs | EC miR-15a/16-1 cKO reduces brain infarcts, BBB leakage, and decreases infiltration of peripheral immune cells | miR-15a/16-1 directly targets claudin-5. EC-selective miR-15a/16-1 deletion enhances claudin-5 levels and reduces M1-type microglia/macrophage infiltration | [65] | |
2020 | let-7g*/miR-98 | Down | Mice | Let-7g* and miR-98 reduce proinflammatory cytokines, let-7g* reduces BBB leakage and improves vascular perfusion function | Both miRs directly target CCL2 and CCL5 cytokines to regulate the cerebral microvessel thickness and perfusion | [80] | |
2020 | let-7g | Down | Mice, BMVEC | Let-7g attenuates inflammation, reduces BBB permeability | Let-7g limits neutrophils infiltration, microglia activation, and neuronal death | [81] | |
2020 | miR-126-3p/5p | Down | Mice | miR-126-3p or -5p reduces brain infarct volume, edema volume, and IgG leakage to attenuate BBB disruption | miR-126-3p and -5p downregulates proinflammatory cytokines and adhesion molecules, and attenuates the decrease of ZO-1 and occludin | [82] | |
2020 | miR-34a | Up | Mice, CECs | Knockout of miR-34a reduces BBB permeability and improves stroke outcomes | miR-34a directly targets cytochrome c and alleviates disruption of tight junctions | [69] | |
2020 | miR-98 | Down | Mice | miR-98 attenuates BBB permeability, reduces infarct size, and improves locomotor impairment | miR-98 ameliorates the infiltration of proinflammatory Ly6CHI leukocytes and microglial polarization | [83] | |
2020 | miR-155 | Up | Mice | miR-155 KO reduces cerebral infarct volume, hemorrhagic burden and improves neurological deficits | miR-155 deficiency reduces hemorrhagic transformation via the effects on BBB integrity and permeability | [76] | |
2020 | miR-668 | Not detected | Rats | miR-668 inhibition reduces the infarct area, BBB permeability, and neurological score | miR-668 inhibition attenuates the levels of NLRP3, ZO-1, and occludin proteins | [84] | |
2020 | miR-182 | Up | Mice, bEnd.3 | miR-182 KO attenuates infarct volume, BBB permeability | miR-182 directly targets mTOR and FOXO1 to exacerbate apoptosis and the loss of TJ proteins ZO-1 and occludin | [85] | |
2020 | miR-503 | Up | Mice, hBMECs | miR-503 downregulation attenuates the neurological injury, BBB damage, brain edema, CBF reduction | miR-503 regulates EC permeability, cell apoptosis, NO, and ROS generation via PI3K/Akt/eNOS pathway or bcl-2/cleaved caspase-3 pathway | [54] | |
2021 | Let-7f | Down | bEnd.3 | Let-7f increases cell viability, inhibits apoptosis, reduces endothelial permeability | Let-7f targets HMGA2 (high mobility group AT-hook 2) to regulate cell viability, apoptosis, TJ proteins (ZO-1 and occludin), endothelial permeability, and BBB function | [86] | |
2021 | miR-30a | Up | Mice, bEnd.3 | miR-30a inhibition reduces infarct volume, ameliorates neurological deficits, decreases BBB permeability, prevents degradation of TJ proteins | miR-30a directly targets the zinc transporter ZnT4 and regulates ZnT4/zinc signaling pathway | [87] | |
2021 | miR-376b-5p | Down | Mice | miR-376b-5p improves the BBB permeability, relieves brain edema and decreases infarct area | miR-376b-5p targets SOX7 to mediate the Wnt/β-catenin signaling | [88] | |
2021 | miR-149-5p | Down | Rats | miR-149-5p decreases neurological defects, tissue damage, and brain water content, and increases BBB integrity | miR-149-5p decreases the level of inflammatory cytokines (TNF-α and IL-6), MMP-2, and MMP-9 | [89] | |
2021 | miR-92b | Down | Rats, BMECs | miR-92b improves neurological function and protects the BBB integrity | miR-92b targets and negatively modulates NOX4 expression to regulate the viability and permeability of ECs | [90] | |
2021 | miR-141-3p | Up | Mice | miR-141-3p inhibition reduces infarct injury might be due to improved BBB integrity | Not specified | [91] | |
Hemorrhagic stroke | 2016 | miR-130a | Up | Mice, BMECs | miR-130a inhibition reduces brain edema, BBB permeability and improves neurological scores | miR-130a level decreases caveolin-1 and increases MMP-2/9 | [55] |
2017 | miR-126 | Down | Rat, BMECs | miR-126-3p inhibits neutrophil infiltration, microglial activation, and neuronal apoptosis | miR-126-3p suppresses phosphoinositide-3-kinase regulatory subunit 2 (PIK3R2), maintains Akt activation, inhibits apoptosis | [106] | |
2016 | miR-132 | Not detected | Mice | miR-132 enhances the expression of claudin-5 and ZO-1, alleviates BBB permeability, neuro-deficits, brain edema, inflammatory response, and neuronal death | miR-132 reduces the level of AChE and enhances the protective effect of ACh on the brain | [223] | |
2018 | miR-27a-3p | Down | Rats, BMECs | miR-27a-3p alleviates behavioral deficits, brain edema, vascular leakage, and leukocyte infiltration | miR-27a-3p suppresses aquaporin-11 (AQP11) | [109] | |
2019 | miR-126-3p | Down | Rats, BMECs | miR-126-3p inhibition impairs BMECs barrier permeability and upregulates VCAM-1 | miR-126-3p direct targets VCAM-1 | [107] | |
2019 | miR-21-5p | Up | Rats, HEK293T | miR‐21‐5p inhibition reduces the neurological defects, cognitive impairment, alleviates BBB permeability, neuronal apoptosis, and neuroinflammation | miR‐21‐5p direct targets DUSP8 and deactivates the p‐ERK/HO‐1 pathway | [103] | |
2020 | miR-126a-3p | Not detected | Rats, MSCs | miR-126 facilitates the differentiation of MSCs into vascular ECs. miR-126-MSC transplantation reduces the neurological severity score, brain water content, and BBB permeability | miR-126-modified MSC alleviates the cell apoptosis, diminishes PAR-1 and MMP-9, enhances ZO-1 and claudin-5 | [108] | |
2020 | miR-193b-3p | Down | Mice, BMSCs | miR-193b-3p mitigates the neurological behavioral impairment, brain edema, neurodegeneration, and BBB permeability | miR-193b-3p suppresses the expression and activity of HDAC3, upregulating the acetylation of NF-κB p65 | [110] | |
2021 | miR-18a | Not detected | Rats, BMECs | miR-18a enhances BBB permeability, brain edema, and impairs neurological functions | miR-18a direct targets RUNX1, and decreases RUNX1, occludin, and ZO-1 | [224] | |
2021 | miR-103-3p | Up | Mice, bEnd.3 | miR-103-3p inhibition reduces BBB permeability, preserves microvascular integrity, and improves long-term neurobehavioral function | miR-103-3p directly interacts with Caveolin-1 and decreases ZO-1 and occludin | [104] | |
2021 | miR-24 | Up | Rats | miR-24 downregulation improves the learning and memory abilities and improves BBB integrity | miR-24 targets HMOX1, miR-24 inhibition increases SOD, decreases MDA, MPO, IL-6, and TNF-α | [105] | |
2021 | miR-26a | Down | Rats | Overexpressing miR-26a in SHED (stem cells from human exfoliated deciduous teeth) attenuates brain water content and BBB permeability in ICH rats | miR-26a direct targets connective tissue growth factor (CTGF), which has close associations to cell apoptosis | [111] | |
TBI | 2014 | miR-21 | Up | Rats | Upregulation of miR-21 improves long-term neurological function, alleviates brain edema, lesion volume, and BBB leakage | miR-21 promotes the expression of VEGF and the Ang-1/Tie-2 axis. miR-21 also inhibits PTEN and activates Akt signaling | [116] |
2015 | miR-21 | Up | Rats | Upregulation of miR-21 improves neurological outcomes, alleviates secondary BBB damage and loss of TJ proteins occludin and claudin-5 | miR-21 activates the Ang-1/Tie-2 axis, promotes the expression of TJ proteins occludin and claudin-5 to stabilize BBB | [117] | |
2016 | miR-21-5p | UP | BMECs | miR-21-5p alleviates BBB leakage, upregulates occludin and claudin-5 expression after scratch injury | miR-21-5p suppresses inflammatory cytokines and NF-kB signaling, inhibits cellular apoptosis, and promotes the Ang-1/Tie-2 axis | [118] | |
2019 | miR-9-5p | Up | Rats, BMECs | Upregulation of miRNA-9-5p improves neurological recovery, alleviates apoptosis, neuroinflammation, and BBB damage | miRNA-9-5p targets Ptch-1, activates the Hedgehog/AKT/GSK3β pathway, and inhibits NF-κB/MMP-9 pathway | [119] | |
SCI | 2015 | miR-27a | Down | Rats | miR-27a attenuates BSCB leakage after I/R injury, and inhibition of miR-27a exacerbates BSCB leakage | miR-27a attenuates TLR4 activation and inflammatory damage to the BSCB | [124] |
2017 | miR-129-5p | Down | Mice | miR-129-5p preserves motor function, prevents BSCB leakage and water content | miR-129-5p targets the high-mobility group box-1 (HMGB1), and decreases toll-like receptor (TLR)-3, interleukin (IL)-1β and TNF-α levels | [125] | |
2018 | miR-155 | Up | Mice | miR-155 deletion reduces central cord edema, improves BSCB integrity, and reduces the incidence of spinal cord paralysis | miR-15a targets Mfsd2a in EC and motorneurons, exacerbates gray matter damage and EC permeability | [56] | |
2018 | miR-199a-5p | Down | Rats | miR-199a-5p improves the limb motor function and reduces BSCB leakage | miR-199a-5p negatively regulates endothelin converting enzyme 1 (ECE1), and regulates caspase-9, Bcl-2, p-JNK, p-ERK signaling | [126] | |
2020 | miR-128-3p | Down | Rats | miR-128-3p ameliorates BSCB leakage and proinflammatory cytokine release, including IL-6, TNF-a, and IL-1β | miR-128-3p directly targets specificity protein 1 (SP1) to alleviate neuroinflammation and cell apoptosis | [127] | |
2020 | miR-429 | Not detected | hCMEC/D3, spinal cord astrocytes | miR-429 inhibition increases TJ protein ZO-1, occludin, and claudin-5 to reduce BSCB permeability | miR-429 negatively regulates KLF6 to mediate TJ protein expression and BSCB permeability | [131] | |
2020 | miR-125a-5p | Not detected | SCMECs | miRNA-125a-5p reduces permeability and EC death rates | miRNA-125a-5p upregulates ZO-1, occludin, and VE-cadherin, and against hypoxia-induced apoptosis | [129] | |
2021 | miR-155 | Not detected | Mice, bEnd.3 | miR-155 promotes EndoMT and aggravates BSCB disruption, and inhibits the expression of TJ proteins (ZO-1, occludin, claudin1, 2, and 5) | miR-155 activates the NF-κB pathway by suppressing SOCS6-induced p65 degradation | [130] | |
2021 | miR-9 | Down | Rats | miR-9 improves neurological function, reduces BSCB disruption and leakage | miR-9 reduces MAP2K3 and Notch2, reduces the release of IL-6 and IL-1β, and cleaved-caspase 3 | [128] | |
2021 | miR-181c-5p | Not detected | rBMECs, spinal cord astrocytes | NHO-1 reduces the BSCB disruption, and levels of miR-181c-5p. miR-181c-5p increases the BSCB permeability under hypoxia | miR-181c-5p directly targets SOX5 (sex determining region Y-box protein 5) | [132] | |
Glioma/brain metastasis | 2014 | miR-181a | Up | GECs | miR-181a overexpression increases BTB permeability | miR-181a direct targets KLF6, and downregulates TJ protein ZO-1, occludin, and claudin-5 | [138] |
2014 | miR-34c | Up | GECs | miR-34c overexpression impairs BTB integrity and increases BTB permeability | miR-34c regulated BTB permeability via MAZ-mediated expression changes of ZO-1, occludin, and claudin-5 | [139] | |
2015 | miR-18a | Down | GECs | miR-18a overexpression increases the BTB permeability | miR-18a directly bound to myocyte enhancer factor 2D (MEF2D), and MEF2D could directly bind to KLF4 promoter to regulate ZO-1, claudin-5, and occludin | [140] | |
2015 | miR-18a | Down | GECs | miR-18a overexpression impairs the integrity and increases the permeability of BTB | miR-18a increases the permeability of BTB via RUNX1-mediated down-regulation of TJ proteins ZO-1, occludin, and claudin-5 | [141] | |
2015 | miR-34a | Up | GECs | miR-34a overexpression increases the permeability of BTB | miR-34a regulates TJ proteins and BTB function by targeting protein kinase Cε | [142] | |
2016 | miR-200b | Down | GECs | miR-200b overexpression inhibits BTB leakage | miR-200b targets RhoA and ROCKII to regulate stress fiber formation and TJ disassembly | [143] | |
2017 | miR-330-3p | Decreased by EMAP-II | GECs | Endothelial monocyte-activating polypeptide-II (EMAP-II) decreases miR-330-3p, which can decrease BTB permeability | EMAP-II increases BTB permeability through inhibiting miR-330-3p, which negatively regulates PKC-α, and suppresses ZO-1, occludin, and claudin-5 | [144] | |
2018 | piR-DQ590027/miR17HG | Down | GECs | piR-DQ590027 overexpression increases the permeability of glioma conditioned normal BBB | piR-DQ590027 bound to and negatively regulates MIR17HG, which bound separately to miR-153 and miR-377 and negatively regulates FOXR2/ZO-1, occludin, and claudin-5 expression | [145] | |
2018 | miR-429 | Down | GECs | miR-429 overexpression decreases the expression of ZO-1, occludin, and claudin-5, and reduces the distribution continuity | miR-429 directly targets ZO-1, occludin, and p70S6K to increase BBB permeability | [146] | |
2018 | piRNA-DQ593109 | Up | GECs | Downregulation of PIWIL1 or piR-DQ593109 increases BTB permeability | Downregulating PIWIL1 and piR-DQ593109 increases BTB permeability through the MEG3/miR-330-5p/RUNX3/ZO-1, occludin, claudin-5 axis | [147] | |
2019 | miR-132-3p | Up | rats, GECs | miR-132-3p increases BTB permeability | miR-132-3p contributes to the increased permeability of BTB by targeting PTEN/PI3K/PKB/Src/Cav-1 axis | [148] | |
Multiple sclerosis (MS) | 2013 | miR-125a-5p | Down | hCMEC/D3, human fetal astrocytes, patients’ brains | miR-125a-5p overexpression increases brain EC barrier function | miR-125a-5p increases VE-cadherin and ZO-1, and reduces TNF-α-mediated ICAM-1 expression and monocyte transmigration through the EC barrier | [168] |
2014 | miR-155 | Up | mice/brain tissue from MS patients | miR-155 knockout reduces CNS extravasation, and endogenous miR-155 partially prevents the cytokine-induced increase in permeability | miR-155 targets cell–cell complex molecules (annexin-2 and claudin-1), and targets cell-to-extracellular matrix interactions (dedicator of cytokinesis 1 (DOCK-1) and syntenin-1 (SDCBP)) | [172] | |
2015 | miR-320a | Down | Patients’ blood samples | MMP-9 is increased, and miR-320a is decreased in B lymphocytes of MS patients during disease relapse compared to remission | miR-320a inhibition upregulates intracellular MMP-9 protein in B cells and increases extracellular secretion | [169] | |
2016 | miR-155 | Up | hCMEC/D3 | Endothelial miR-155 upregulates the leukocytes extravasation across the inflamed BBB | miR-155 positively regulates VCAM1 and ICAM1 levels | [173] | |
2017 | miR-126&-126* | Down | hCMEC/D3 | Reduction of endothelial miR-126 and miR-126* enhances firm monocyte and T cell adhesion to ECs | miR-126* and miR-126 downregulation increase E-selectin and VCAM1, respectively. miR-126 overexpression reduces VCAM1 and CCL2 expression | [170] | |
2021 | miR-155 from CD8+ T cells | Down | Relapsing–Remitting MS patients’ samples | miR-155 is downregulated, while ICAM-1 and ITGB2 are upregulated | Downregulation of miR-155 correlates with upregulation of surface receptors and cytotoxic proteins in CD8+T cells | [57] | |
AD/VCID | 2016 | miR-107 | Down in AD | HBMECs | Overexpression of miR-107 abrogates Abeta-induced disruption of BBB and endothelial cell dysfunction | miR-107 direct targets and downregulates endophilin-1, and regulates BBB permeability and the expression of ZO-1, occludin, and claudin-5 | [177] |
2018 | miR-501-3p | Up in VCID | Mice | miR-501-3p inhibition attenuates BBB disruption within the white matter and ameliorates memory deficits | miR-501-3p directly targets human ZO-1 and downregulates trans-endothelial electric resistance | [182] | |
2018 | miR-126 | Down in VCID | Mice | EC-miR-126 cKO exacerbates cognitive impairment, decreases CBF, myelin and axon density, increases inflammation, water channel, and glymphatic impairment | miR-126 knockout increases endothelial MMP-9 and TLR4 inflammatory factor, downregulates AQP-4, and delays penetration and clearance of CSF into the brain via paravascular pathways | [181] | |
2018 | miR-96 | Up | Mice, hBMECs | High levels of GM-CSF downregulates ZO-1 and facilitates the infiltration of peripheral monocytes across the BBB | miR-96 targets ETS transcription factor ERG to downregulate ZO-1 expression | [179] | |
2019 | miR-181a | Down in AD | APP/PS1 mice, mBVPs | miR-181a overexpression ameliorates cognitive deficits and amyloid plaque deposition | miR-181a attenuates pericyte apoptosis and BBB breakdown by suppressing FOXO1 | [59] | |
2019 | miR-124 | Down in AD | APP/PS1 mice | miR-124 rescues BBB breakdown, promotes angiogenesis, reduces Aβ deposition, and alleviates learning and memory deficit | miR-124 targets and suppresses C1ql3 to upregulate expression of ZO-1 to enhance BBB integrity | [178] | |
2019 | miR-424-5p | Up in AD | hCMEC/D3 | miR-424-5p silencing decreases BBB permeability | miR-424-5p silencing upregulates TJ proteins ZO-1 and occludin by targeting Endophilin-1 | [180] | |
Brain infection | 2013 | miR-101 | Up | BMVECs | HIV-1 Tat C increases the expression of miR-101 and increases EC permeability | miR-101 directly targets VE-cadherin, and VE-cadherin levels govern the expression of claudin-5 | [185] |
2015 | miR-98 and let-7g* | Down | Mice, BMECs | Overexpression of let-7 and miR-98 reduces leukocyte adhesion to and migration across the endothelium, and increases BBB tightness | miR-98 and let-7g* diminishes levels of pro-inflammatory cytokines by targeting secreted monocyte CCL2 and CCL5 | [186] | |
2017 | miR-155 | Up | Mice | miR-155 deficiency improves survival and preserves BBB integrity in experimental cerebral malaria | miR-155 deficiency decreases inflammation and endothelial activation | [187] | |
2018 | miR-1303 | Down | Monkeys, HUVECs | CA16 infection increases the degradation of junctional complexes (claudin-4, claudin-5, VE-cadherin, and ZO-1) | miR-1303 directly targets MMP9, CA16 penetrates the BBB by downregulating miR-1303 and upregulating MMP9 | [188] | |
Diabetes | 2017 | miR-Let7A | Down | bEnd.3 | miR-Let7A overexpression attenuates EC monolayer integrity under high glucose condition | miR-Let7A overexpression prevents cell death and loss of TJ proteins (claudin-5 and ZO-1) and attenuates proinflammatory response and nitrite production | [195] |
2019 | miR-200a | Down | Mice, hBMECs | Diabetes increase HDAC3 expression, and HDAC3 inhibition reduces diabetes-induced BBB permeability and rescues junctional protein expression in db/db mice | HDAC3 inhibition is protective against BBB permeability via miR-200a/Keap1/Nrf2 axis in db/db mice | [196] | |
SAE | 2020 | miR-181b | Up | Rats, rBMECs, rat brain astrocytes | miR-181b downregulation reduces BBB damage | miR-181b negatively targets S1PR1 and NCALD to worsen BBB impairment | [198] |
2020 | miR-370-3p | Up | Mouse and patient samples | CLP-induced SAE increases mouse brain and plasma miR-370-3p levels with BBB permeability deficits | High plasma miR-370-3p was associated with elevated TNF-a and brain apoptosis | [60] | |
2021 | miR-126 | Down | Rats | miR-126 overexpression improves the neurobehavioral score, reduces the brain tissue water content and BBB permeability | miR-126 overexpression increases claudin-5 and occludin, decreases TNF-α, IL-6, IL-1β, and increases IL-10 by inhibiting the NF-kB signaling pathway | [199] | |
Shear stress | 2017 | miR-27b | Up | Mice | miR-27a/b inhibition reduces pericyte adhesion, pericyte coverage, and barrier functions, and increases the water content and vessel permeability | Shear stress-regulated miR-27b promotes the interaction of endothelial cells with pericytes, partly by repressing repulsive proteins SEMA6A and SEMA6D | [200] |
Development | 2017 | miR-285 | Required for BBB | Drosophila | Loss of miR-285 leads to defective BBB with increased subperineurial glia (SPG) ploidy and disruptive septate junctions | miR-285 directly targets the Yki cofactor Mask (Multiple Ankyrin repeats Single KH domain (Mask)) to suppress Yki activity and down-regulates the expression of its downstream target cyclin E | [201] |
Development | 2017 | miR-132 | Required for BBB | Zebrafish larvae, primary rat brain cells | miR-132, secreted from neurons, regulates the brain vascular integrity by affecting adherens junction proteins rather than transcytosis or pericytes | miR-132 regulates VE-cadherin by directly targeting eukaryotic elongation factor 2 kinase (eef2k) to maintain brain vascular integrity | [202] |
Aging | 2020 | miR-195 | Down | Mice | miR-195 downregulation increases BBB leakage, miR-195 overexpression improves BBB integrity | miR-195 suppresses thrombospondin-1 (TSP1), which activates selective autophagy to decrease claudin-5 and ZO-1 | [203] |
Tuberous sclerosis complex | 2020 | miR-146a and 147b | Not detected | Patient brains, tuber-derived cultures | BBB dysfunction with increased albumin and CD163 is associated with high levels of MMPs and TIMPs (protein expression of MMP2, 3, 9, and 14 and TIMP1, 2, 3, and 4) in cortical tubers | miR-146a and miR-147b can rescue IL-1b-induced dysregulation of MMP3, TIMP2, TIMP3, and TIMP4 in tuber-derived TSC cultures | [204] |
RCVS | 2021 | miR-130a-3p | Up | hCMEC/D3 | High levels of circulating miR-130a-3p is associated with BBB disruption in patients with reversible cerebral vasoconstriction syndrome, miR-130-3p overexpression induces EC permeability | miR-130a-3p increases BBB permeability in a dose-dependent manner | [205] |
May be related to COVID-19 | 2021 | miR-24 | Not detected | hBMECs | miR-24 overexpression reduces VEGFA-induced endothelial permeability | miR-24 directly targets and negatively regulates Neuropilin-1 | [208] |