Introduction
EVs: biogenesis, composition, and secretion
Biogenesis of EVs
Contents of EVs
Content sorting mechanisms of EVs
Uptake of EVs
Pathological roles of EVs in NDs
Cell origin | Disease | Up-regulated cargos | Down-regulate cargos | Outcome of EV cargo alteration | References |
---|---|---|---|---|---|
Neuron | AD | P-T181-tau, Aβ1−42, cathepsin D | – | Promoting Aβ deposition and NFT formation | [84] |
AD | APP mRNA & protein | – | Facilitating the production of Aβ | [10] | |
AD | miR-124, miR-155, miR-146a, miR-21, miR-125b | – | Inducing microglial activation and pro-inflammatory cytokine release | [87] | |
AD | – | miR-185 | Elevating APP expression levels | [10] | |
PD | α-syn | – | Inducing neurotoxicity and α-syn-rich Lewy bodies formation | [272] | |
PD | Rab8b, Rab31 | – | Contributing to non-motor symptoms in PD pathology including hearing loss | [123] | |
PD | 20 S Proteasome complex, PARK7, Gelsolin, Amyloid P component, Clusterin | – | Participating in PD onset and progression | [124] | |
PD | miR-19a-3p, miR-155 | – | Mediating α-syn-induced inflammatory responses | [121] | |
ALS | mutant SOD1 | – | Inducing mitochondrial toxicity | [138] | |
ALS | DPRs, TDP-43 | – | Inducing astrocyte toxicity and neurodegeneration | [139] | |
ALS | miR-4736, miR-4700-5p, miR-1207-5p, miR-4739, miR-4505, miR-24-3p, miR-149-3p, etc. | miR-1268a, miR-2861, miR-4508, miR-4507, miR-3176, miR-3911, miR-150-3p, etc. | Disturbing neuroplasticity and enhancing neural damage | [141] | |
HD | mutant HTT | – | Inducing neurodegeneration | [156] | |
Astrocyte | AD | p-Tau | – | Enhancing the formation of NFT | [95] |
AD | BACE1, complement proteins | – | Promoting Aβ cleavage and neuronal damage | ||
PD | – | miR-200a-3p | Inhibiting c-Jun N-terminal kinase cell death pathway | [129] | |
ALS | mutant SOD1 | – | Inducing selective motor neuron death | [146] | |
ALS | – | miR-494-3p | Unlocking SEMA3A-induced motor neuron degeneration | [147] | |
ALS | IL-6 | – | Exacerbating pro-inflammatory responses of neuroglial cells | [148] | |
HD | – | CRYAB | Suppressing EV secretion | [273] | |
Microglia | AD | Human tau | – | Spreading of tau protein | [80] |
AD | TREM2 | – | Changing environment around Aβ and promoting microglia to phagocytose Aβ | [114] | |
AD | APP/Aβ, P2RY12, TMEM119, FTH1, TREM2 | – | Stimulating microglial activation and contributing to Aβ deposition | ||
AD | Cholesterol, BMP, MhCer lipid species | DHA-containing polyunsaturated lipids | Inducing defect in acyl-chain remodeling | [112] | |
AD | miR-28-5p, miR-381-3p, miR-651-5p, miR-188-5p | – | Enhancing neuroinflammation and cellular senescence | [112] | |
PD | α-syn | – | Spreading α-syn oligomers through microglia-neuron α-syn transmission | [130] | |
PD | MHC class II molecules, TNF-α | – | Triggering neuroinflammation and dopaminergic neurodegeneration | ||
ALS | mutant SOD1 | – | Inducing neurotoxicity and motor neuron death | [150] | |
ALS | HMGB1, miR-155, miR-146a | – | Activating microglia and impairing mitophagy | [151] | |
Oligodendrocyte | PD | α-syn | – | Inducing neurotoxicity and formation of α-syn-rich Lewy bodies | [136] |
Pathological roles of EVs in AD
Pathological roles of neuron-derived EVs (NDEVs) in AD
Pathological roles of astrocyte-derived EVs (ADEVs) in AD
Pathological roles of microglia-derived EVs (MDEVs) in AD
Pathological roles of EVs in PD
Pathological roles of NDEVs in PD
Pathological roles of ADEVs in PD
Pathological roles of MDEVs in PD
Pathological roles of oligodendrocyte-derived EVs (ODEVs) in PD
Pathological roles of EVs in ALS
Pathological roles of NDEVs in ALS
Pathological roles of ADEVs in ALS
Pathological roles of MDEVs in ALS
Pathological roles of EVs in HD
Pathological roles of NDEVs in HD
Pathological roles of ADEVs in HD
Pathological/beneficial roles of peripheral EVs in NDs
EVs as novel biomarkers for the diagnosis of NDs
Disease | Down-regulated | Up-regulated | AUC | Sensitivity (%) | Specificity (%) | Specimens | Species | References |
---|---|---|---|---|---|---|---|---|
AD | APOC3, APOH, C4BPα, CO3, KV230 | AACT, CO9, IGHM, K2C6A | – | – | – | Serum EVs | Human | [172] |
AD | miR-342-3p, miR-23b-3p, miR-24-3p, miR-125b-5p | miR-141-3p, miR-342-5p | 0.919 | 81.7 | – | Serum EVs | Human | [174] |
AD | BACE-1-AS-LncRNA (in Pre-AD) | BACE-1-AS-LncRNA (in late AD) | – | 75 (pre-AD) 68 (late-AD) | 100 100 | Plasma EVs | Human | [177] |
AD | miR-135a, miR-384 | miR-193b | – | 99 | 95 | Plasma EVs | Human | [175] |
AD | miR-138-5p, miR-342-3p | miR-29c-5p, miR-143-3p, miR-335-5p, miR-485-5p | 0.880 | – | – | Serum EVs | Human | [176] |
AD | – | Aβ42/40 miR-384 | 0.973 0.909 | – | – | Blood NCAM+ NDEVs | Human | [178] |
AD | – | miR-29c-3p | 0.927 | Blood NCAM+ NDEVs | Human | [179] | ||
AD | miR-212 miR-132 | – | 0.84 0.77 | 92.2 | 69 | Blood L1CAM+ NDEVs | Human | [180] |
AD | – | tau, p-T181-tau, p-S396-tau, Aβ1−42 | 0.99 | 96 | Blood L1CAM+ NDEVs | Human | [181] | |
PD | – | α-synuclein | 0.724 | 76.8 | 53.5 | Plasma EVs | Mouse | [183] |
PD | Prp | – | – | – | – | Plasma EVs | Human | [184] |
PD | miR-1 miR-19b-3p | miR-153, miR-409-3p miR-10a-5p let-7 g-3p | 0.920 0.705 0.990 0.900 | – | – | CSF EVs | Human | [185] |
PD | – | α-synuclein, clusterin | 0.98 (PD VS. atypical PD) | – | – | Serum EVs | Human | [119] |
PD | α-synuclein (in PD VS. MSA) | 0.902 PD VS. MSA) | – | – | Blood MOG+ ODEVs, L1CAM+ NDEVs | Human | [136] | |
ALS | – | CORO1A | – | – | – | Plasma EVs | Human | [186] |
ALS | – | TDP-43, NFL | – | – | – | Plasma EVs | Human | [187] |
ALS | miR-146a-5p | – | – | – | – | CSF EVs | Human | [189] |
ALS | – | miR-15a-5p miR-193a-5p | 0.976 0.844 | 92.9 80.0 | 91.7 88.9 | Plasma EVs | Human | [190] |
ALS | miR-10b-5p miR-29b-3p | miR-146-5p miR-199a-3p, miR-199a-5p miR-151a-3p, miR-151a-5p | – | – | – | Plasma L1CAM+ NDEVs | Human | [191] |
EVs as novel biomarkers for the diagnosis of AD
EVs as novel biomarkers for the diagnosis of PD
EVs as novel biomarkers for the diagnosis of ALS
EVs as novel biomarkers for the diagnosis of HD
EV-based therapeutic strategies in the treatment of NDs
Pathogenic EVs as targets for the treatment of NDs
Stem cell-derived EVs as potential therapeutic agents for the treatment of NDs
Cell origin | Disease | Therapeutic cargos | Targets | Administration mode | Models | Outcomes | References |
---|---|---|---|---|---|---|---|
MSC | AD | miR-29 | HDAC4 | Weekly intravenous injection for 4 weeks | hAPP-J20 mice | Improve cognitive function, decrease Aβ levels, inhibit astrocyte activation. | [208] |
MSC | AD | NEP | Aβ | Co-culture | N2a cells | Promote Aβ degradation | [209] |
MSC | AD | miR-223 | PTEN | Co-culture | Aβ-treated SH-SY5Y cells | Inhibit neuronal cell apoptosis, enhance cell migration | [213] |
MSC | AD | – | – | Co-culture | TG2576 mouse-derived neurons | Reduces Aβ levels, attenuates apoptosis, increases neurite outgrowth | [214] |
MSC | AD | – | – | Intracerebroventricle injection once per 2 days for 2 weeks | APP/PS1 mice | Mitigate neuroinflammation and neural impairment | [221] |
MSC | PD | – | – | SNpc and striatum injection | 6-OHDA-injected rats | Attenuate fine motor deficits, protects against TH damage | |
MSC | PD | – | – | Diluted in inactivated OP50 | Two C. elegans models | Reduce α-syn levels | [211] |
MSC | PD | – | – | Intravenous injection every 3 days for 8 weeks | 6-OHDA-injected rats | Improve the behavioral deficits, reduce dopaminergic neuron loss | [215] |
MSC | PD | – | SMAD3, p38 MAPK | Subcutaneous injection into the right forelimb | MPTP-injected mice | Promote angiogenesis | [217] |
MSC | PD | – | – | Co-culture | 6-OHDA-treated SH-SY5Y cells | Protect neuronal cells from oxidative damage | [223] |
MSC | ALS | – | – | Co-culture | Mutant SOD1-NSC-34 cells | Promote cell survival, inhibit apoptotic genes | [219] |
MSC | ALS | – | – | Intravenous and intranasal injection | SOD1(G93A) mice | Improve motor performance, inhibit neurodegeneration | [220] |
MSC | ALS | – | – | Co-culture | Mutant SOD1-overexpressing NSC-34 cells | Protect NSC-34 cells from oxidative damage and apoptosis | [224] |
NSC | AD | – | – | Single retro-orbital vein injection | 5×FAD mice | Reduce Aβ deposition, rescue the cognitive defects | [228] |
NSC | AD | – | – | Bilateral injection into the lateral ventricles | APP/PS1 mice | Rescue the cognitive defects | [229] |
NSC | PD | – | – | Injection into the SN region | 6-OHDA-induced mice | Reduce ROS levels and 6-OHDA-induced dopaminergic neuronal loss | [230] |
NBC | AD | GSLs | Aβ | Brain infusion for 2 weeks | APPSweInd mice | Decrease Aβ pathologies | [239] |
SHED | PD | – | – | Co-culture | 6-OHDA-treated neuron | Suppress 6-OHDA-induced apoptosis | [238] |
Mesenchymal stem cell-derived EVs as potential therapeutic agents for the treatment of NDs
Neural stem cell (NSC)-derived EVs as potential therapeutic agents for the treatment of NDs
Potential therapeutic effects of EVs derived from other stem cell types on NDs
Engineered EVs as a potential drug delivery platform for treatment of NDs
Cell/tissue origin | Disease | Surface modification | Loaded cargos | Therapeutic Targets | Administration mode | Models | Outcomes | References |
---|---|---|---|---|---|---|---|---|
Dendritic cell | PD | RVG | α-syn-siRNA | α-syn | Intravenous injection | α-Syn Tg mice | Reduce intraneuronal α-syn aggregates | [247] |
Dendritic cell | PD | RVG | α-syn-shRNA | α-syn | Intravenous injection | Syn PFFs-injected mice | Reduce α-syn aggregation, decrease neuronal death, alleviate PD symptoms | [249] |
U87 cell | HD | – | Htt siRNA | Htt | Infusion into the striatum for 7 days | Wild type mice | Reduce Htt expression | [248] |
MSC | AD | RVG | miR-146a | NF-κB pathways | Intracerebroventricular injection for 2 times | APP/PS1 mice | Inhibit pro-inflammatory responses of astrocytes and microglia | [167] |
MSC & 293T cell | AD | – | miR-29b | BACE1, BIM | Bilateral injection into hippocampal CA1 region | Aβ-treated model rats | Enhance spatial learning and memory | [251] |
MSC | AD | – | miR-22 | GSDMD | Intravenous injection every 7 days | APP/PS1 mice | Enhance behavioral performance, repress neuroinflammation | [252] |
MSC | PD | – | miR-188-3p | CDK5, NLRP3 | Intravenous injection for 5 days | MPTP-induced PD mice | Suppress autophagy and pyroptosis | [253] |
293T cell | PD | – | Catalase mRNA | ROS | Implantation of EV producers into the brains | 6-OHDA-injected mice | Protect neurons against neurotoxicity, inhibit neuroinflammation | [246] |
Macrophage | PD | – | Redox catalase | ROS | Intranasal injection for 10 times every other day | 6-OHDA-injected mice | Eliminate ROS and display neuroprotective effects | [254] |
Macrophage | AD | Mannose | Gemfibrozil | Aβ | Intraperitoneal injection for 7 consecutive days | Aβ-injected mice | Promote Aβ clearance by microglia, improve learning and memory ability | [267] |
Blood | PD | – | Dopamine | Dopamine receptors | Intravenous injection | 6-OHDA-injected mice | Improve dopaminergic neurons, ameliorate PD phenotype | [255] |
NSC | MS | PDGFA | Montelukast | GPR17 | Intranasal injection every day for 2 weeks | Cuprizone-treated mice | Promote myelin regeneration | [257] |
NSC | MS | – | Bryostatin-1 | GPR17 | Intravenous injection | Cuprizone-treated mice | Promote myelin regeneration | [256] |