The Exosome-Mediated PI3K/Akt/mTOR Signaling Pathway in Neurological Diseases
Abstract
:1. Introduction
2. Study Design and Methods
3. Neurodegenerative Diseases, Neurological Disorders, and Exosomes: Focusing on Pivotal Functions of PI3k/Akt/mTOR Signaling Pathway
3.1. Exosomes and Alzheimer’s Disease, Cognition, Learning and Memory
3.2. Exosomes and Stroke
3.3. Exosomes and Spinal Cord Injury
3.4. Exosomes and Traumatic Brain Injury
3.5. Exosomes and Other Neurological Disorders
4. Conclusions and Future Perspective
Author Contributions
Funding
Conflicts of Interest
References
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Source of Exosomes | Cargo or Intermediate Molecule | Disease | Method (In Vitro/In Vivo) | Dose/Route of Administration | Mechanism of Actions and Outcomes | References |
---|---|---|---|---|---|---|
ADSC | _____ | AD | in vitro: PC12 cells | 10, 50 and 100 μg/mL | ↑p-PI3K, p-Akt, CD29, CD44, CD73, CD105, cell proliferation, and migration; ↓CD45, HLA-DR, and cell apoptosis | [44] |
BMSCs | GDF-15 | AD | in vitro: SH-SY5Y cells | _____ | ↑Cell viability, Akt/GSK-3β/β-catenin pathway; ↓Apoptosis, TNF-α, IL-6, IL-1β, and IL-8 | [45] |
Macrophage cell line (RAW 264.7) | Curcumin | AD | in vivo: Okadaic acid-induced AD in C57BL/6 mice; in vitro: hCMEC/D3 cells | 0.4 mg/kg, single i.v. dose, and 100 μg/mL, i.p. for 7 days | ↑Curcumin solubility, stability, bioavailability, cellular uptake and BBB-crossing, p-Akt, p-Ser9 GSK-3β; ↓Learning deficiencies, cognitive decline, escape latency, cell apoptosis, tau hyperphosphorylation, p-Ser396 tau, neuronal injury, Bax and c-caspase 3; | [46] |
HucMSCs | miR-223 | AD | in vitro: Aβ1–40-induced injury in SH-SY5Y cells under hypoxic conditions | 2 μg per 1 × 105 recipient cells | ↑p-Akt; ↓Apoptosis, scratch area, IL-6, IL-1β, TNF-α, CRP, and PTEN | [47] |
NSC | _____ | HFD-related cognitive decline | in vivo: male C57BL/6 mice | 1.5 μg per nostril, 3 times per week | ↑BDNF, nNOS, Sirt1, Egr3, RelA, and pTrkB; ↓Memory impairment | [48] |
MSCs | miR-132-3p | VD | in vivo: VD-induced in male C57BL/6 mice; in vitro: OGD-injured neurons | 1 × 1010 particles/100 μL, via the tail vein once every 7 days for 21 days | ↑Cognitive function, neuron number, dendritic spine density, synaptic plasticity, Ras, p-Akt, p-GSK-3β, and neurite elongation; ↓Aβ, p-tau, RASA1, and apoptosis | [49] |
MSCs | miR-17-92 | Stroke | in vivo: 2 h intraluminal filament-induced MCAO in Wistar rats; Ex-vivo rat organotypic brain slice culture model | 3 × 1011 particles/rat, i.v. | ↑GAP-43 immunoreactivity, cortical and intracortical axonal density, myelin density, neuronal plasticity, contralesional axon number and total length, CST axonal remodeling, and functional recovery ↓Time to remove the adhesive tabs, mNSS score, and lowest threshold value of ICMS; ↑MBP+ myelin and NFH+, PTEN/PI3K/Akt/mTOR pathway | [53] |
MSCs | miR-17–92 | Stroke | Wistar rats were subjected to 2 h intraluminal filament-induced MCAO | 100 μg total exosome protein or 3 × 1011 particles per rat, i.v. | ↑Functional recovery, axonal density, p-NF-H immunoreactive area, synaptophysin immunoreactivity, primary and secondary neurite branching, spine density, dendritic plasticity, neurogenesis, oligodendrogenesis, p-Akt, p-mTOR, and p-GSK-3β; ↓mNSS score, number of Foot-fault and PTEN level | [54] |
Healthy rat serum-derived exosomes | _____ | Stroke | in vivo: Focal cerebral ischemia induced by the intraluminal suture MCAO method in SD rats in vitro: OGD/R injury model in bEnd.3 immortalized mouse brain endothelial cells | 800 μg/kg, i.v. 50 μg/mL | ↑Neurobehavioral scores, total moving distance, neuronal spine density, claudin-5, ZO-1, Bcl-2/Bax ratio, p-Akt/Akt and SQSTM1/p62 expression, ↓Infarct volumes, %distance and %time in center, BBB leakage, Evans blue dye extravasation, MMP-9, cleaved caspase-3 and LC3B-II/LC3B-I ratio; ↑SQSTM1/p62 expression, ↓Apoptotic cells, TUNEL+/CD31+ cells, cleaved caspase-3 and LC3B-II/LC3B-I ratio | [55] |
MSCs | miR-132-3p | Ischemic stroke | in vivo: Focal ischemic stroke induced by transient MCAO in C57BL/6 mice in vitro: H/R injury model in mouse brain microvascular endothelial cells | 1 × 1010 particles/100 μL in PBS via the tail vein, i.v. 50 μg/mL | ↑cMVD and CBF;↓ROS, apoptosis, Evans blue dye extravasation, brain water content, infarct volume, NDS, and BBB disruption; ↑Ras, p-PI3K/PI3K, p-Akt/Akt and p-eNOS/eNOS, ZO-1, and Claudin-5; ↓RASA1, ROS, paracelluar permeability and apoptosis | [56] |
BMSCs | miR-146a-5p | ICH | in vivo: Collagenase type IV-induced ICH in male SD rats, by an intrastriatal injection | 100 μg/mL, 100 μg via the tail vein, i.v. | ↑SOD and neurological function; ↓Microglia M1 polarization, iNOS, COX-2, MCP-1, IRAK1, NFAT5, TNF-α, IL-1β, IL-6, MPO-positive cells, MDA, OX42-positive cells, Iba-1+/MHC-II+, apoptotic, and degenerative neurons | [57] |
MSCs | miR-133b | ICH | in vivo: An autologous arterial blood ICH model in adult male SD rats | 100 μg via the tail vein, i.v., 72 h after ICH | ↑p-ERK1/2/ERK1/2 and p-CREB/CREB; ↓RhoA expression, neuronal apoptosis and neurodegenerative neurons | [58] |
ADSCs | miR-140-5p | SAH | in vivo: SAH-induced neurological dysfunction in rat in vitro: TDP-43-induced neuronal injury | _____ | ↑Cell viability and PI3K/Akt activation; ↓IGFBP5 expression and apoptosis | [59] |
HucMSCs | miR-206-knockdown | SAH | in vivo: SAH-induced EBI in double blood injection model in SD rats | 200 μL PBS containing 400 μg exosomes, i.v. injected into the femoral vein 1 h after SAH | ↑Bcl-2, BDNF, TrkB, and p-CREB; ↓Bax, caspase-8, neurological deficit, brain edema, and neuronal apoptosis | [60] |
SC | _____ | Cerebral I/R injury | in vivo: Focal cerebral I/R induced by the improved Longa method in rats | _____ | ↑Latency for the novel arm, IFN-γ, and Bcl-2; ↓Novel entries, IL-1α, IL-2, TNF-α, Bax, cleaved caspase-3, cleaved caspase-9, CytC, PI3K, Akt, and neural cell apoptosis | [61] |
ATCs | miR-34c | Cerebral I/R injury | in vivo: Wistar rats MCAO model in vitro: OGD/R model in N2a mouse neuroblastoma cells | 20 and 30 μg/mL via the tail vein after ischemia, 20 μM | ↑Nissl bodies and c-fos positive cell numbers; ↓Neuronal injury, NDS, infarct volume, brain water content, IL-6, IL-8, and TNF-α; ↑Cell proliferation, EdU positive cell index, and TLR7; ↓Bax, cleaved caspase-3, cleaved PARP, apoptosis, and NF-κB/MAPK axis | [62] |
BMSCs | _____ | Cerebral I/R injury | in vitro: OGD/R model in PC12 cells | 10 μg/mL | ↑Cell viability, autophagic flux, p-AMPK/AMPK; ↓LDH, morphological changes, pyroptosis, NLRP3, ROS, cleaved caspase-1, IL-1β, GSDMD-N, p-mTOR/mTOR, and P62 | [63] |
ATCs | miR-361 | Cerebral I/R injury | in vivo: Wistar rats reversible MCAO model in vitro: OGD/R model in PC12 mouse neuroblastoma cells | 2 mL exosomes (30 μg/mL) via the caudal vein, twice a week for 2 weeks 30 μg/mL | ↑Nissl bodies, C-fos and neuronal viability; ↓Nerve damage, NDS, brain water content, infarct volume, cerebral edema, apoptosis, AMPK and mTOR mRNA and protein levels; ↑Cell activity, cell proliferation, and EdU positive cell index; ↓Apoptosis, Bax, cleaved caspase-3, cleaved PARP, CTSB, AMPK and mTOR mRNA and protein levels | [64] |
BMSCs | miR-29b-3p | Hypoxic-ischemic brain injury | in vivo: Cerebral ischemia induced by MCAO method in SD rats in vitro: OGD/R injury model in rat primary cortical neurons and BMECs | 100 μg/kg/day intracerebroventricular stereotactic injection 2 h after the MCAO model, every day for 3 days | ↑Bcl-2, VEGFA, VEGFR2, angiogenesis, and p-Akt/Akt; ↓Apoptotic cells, Bax, cleaved caspase-3, infarct volume, MVD, and PTEN; | [65] |
Neuron, EC, NPC and ATC differentiated from H9 hES | _____ | Ischemia | OGD-induced injury in H9 hES derived neurons | 100 μg/mL | ↑Neuronal survival rate, p-PI3K p85, p-Akt, p-mTOR, Bcl-2, and basal neuronal synaptic transmission; ↓Neuronal damage, p-AMPK, COX-2, iNOS, TNF-α, Bax, and cleaved caspase-3 | [66] |
EPCs | miR-126 | Diabetic ischemic stroke | H/R and HG-induced injury in human astrocytes | 3 × 109 particles/mL | ↓Cytotoxicity, ROS and lipid peroxidation | [67] |
Source of Exosomes | Cargo or Intermediate Molecule | Disease | Method (In Vitro/In Vivo) | Dose/Route of Administration | Mechanism of Actions and Outcomes | References |
---|---|---|---|---|---|---|
BMSCs | miR-26a | SCI | in vivo: SCI induced in SD rats in vitro: PC12 cells | 200 μg in 200 μL PBS via tail vein injection 20 μg/mL for 48 h | ↑Axonal regeneration, neurogenesis, functional recovery, BBB scores, MEP amplitudes, neurofilament density, Tuj-1, p-Akt, p-PI3K, p-mTOR, p-S6K, and p62; ↓Glial scarring, GFAP, astrocyte inflammation, autophagy, p-AMPK, p-ULK1, p-IKB, and p-p65; ↑Neurofilament generation, nerve regeneration, p-Akt, p-PI3K, and p-mTOR, ↓PTEN, autophagy, p-AMPK, p-ULK1, p-IKB and p-p65 | [84] |
BMSCs | miR-338-5p | SCI | in vivo: SCI induced in SD rats in vitro: H2O2-induced oxidative stress injury in PC12 cells | 100 µg (50 µg microinjected to injured site +50 µg via the tail vein) in PBS at 5 min and 1 h after SCI, 100 μg of total protein | ↑NF-M and GAP43; ↓MAG and GFAP; ↑Cell viability, SOD, NF-M, GAP43, Bcl-2, cAMP, Rap1, p-Akt, and p-PI3K; ↓Apoptosis, ROS, MAG, GFAP, Bax, cleaved caspase-3, and Cnr1 | [85] |
BMSCs under hypoxia | miR-216a-5p | SCI | in vivo: SCI induced in C57BL/6 mice in vitro: LPS-stimulated BV2 microglial cells and primary microglia | 200 μg of total protein via tail vein injection 200 μg/mL | ↑Functional recovery, BMS score, gait recovery, motor coordination, NeuN-positive neurons, MEP amplitudes, IL-4, IL-10, TGF-β, Arg1, CD206, YM1/2, and M1 to M2 polarization; ↓Neurofilament 200, lesion volume, iNOS, TNF-α, IL-1β, and IL-6; ↑IL-4, IL-10, Arg1, CD206, YM1/2, M1 to M2 polarization, TGF-β, p-Akt, and p-PI3K; ↓TNF-α, IL-1β, IL-6, iNOS, TLR4, p-P65, and MyD88; | [86] |
GIT1-BMSCs | _____ | SCI | in vivo: SCI induced in SD rats in vitro: Glutamate-induced injury model in neuronal cells | 200 μg of total protein via tail vein injection 100 µg/mL | ↑Nissl bodies, neural regeneration, BBB score, motor function, Bcl-2, and P-Akt; ↓Apoptosis, glial scar formation, TNF-α, IL-1β, IL-6, Bax, and cleaved caspase-3; ↑Bcl-2; ↓TUNEL-positive cells, neural apoptosis, Bax, cleaved caspase-3, and caspase-9 | [87] |
MSCs | _____ | SCI | in vivo: SCI induced in SD rats in vitro: Astrocytes isolated from SCI rats | 1 × 106 in 200 μL PBS via tail vein injection, 5 × 104 | ↑Functional recovery, MBP, BBB scores, Syn, and NeuN; ↓Lesion size, morphological phenomena, p65+ nuclei, A1 astrocytes, TNF-α, IL-1α, IL-1β, C3, GFAP, TUNEL-positive cells, p-IKBα, and p-p65 | [88] |
MSCs | miR-126 | SCI | in vivo: SCI induced in SD rats in vitro: OGD injury model in HUVECs | 100 µg of total protein in 0.5 mL PBS via tail vein injection 10 µg | ↑Functional recovery, VEGF, angiogenesis, neurogenesis, blood vessels number and connectivity value, Bcl-2, NeuN, Sox2, and Nestin positive cells; ↓Lesion volume, incorrect steps, apoptosis, SPRED1, PIK3R2, Bax and cleaved caspase-3; ↑Angiogenesis and HUVECs migration; ↓SPRED1 and PIK3R2 | [89] |
Neuron-derived exosomes | miR-124-3p | SCI | in vivo: SCI induced in C57BL/6 mice in vitro: Primary microglial cultures and MCM, primary astrocyte cultures and primary neuronal cultures | 200 μg of total protein in 200 μL of PBS via tail vein injection 200 μg/mL | ↑Functional recovery, BMS score, gait recovery, motor coordination, MEP amplitudes, and hind limb alternation; ↓Forelimb dependence, axonal damage, TNF-α, IL-1α, IL-6, IL-1β, C1q, M1 microglia, iNOS, C3, and A1 astrocytes; ↑p-PI3K and p-Akt; ↓M1 microglia, iNOS, and p-P65 | [90] |
NSCs | FTY720 | SCI | in vivo: SCI induced in SD rats in vitro: SCMECs hypoxic model | 20 μg in 0.3 mL PBS via tail vein injection 20 μg/mL | ↑Locomotor function, complete tissue structure, claudin-5, and Bcl-2; ↓Edema formation, inflammatory cell infiltration, SCI lesion, neuronal cell apoptosis, AQP4, and Bax; ↑ZO-1 and p-Akt ↓PTEN and SCMEC permeability | [91] |
Primary SCDEs | _____ | SCI | in vivo: SCI induced in mice in vitro: H2O2-induced injury in spinal cord astrocytes | 0.1 μg/μL in 100 μL of DPBS via tail vein injection, three times a week for 4 weeks | ↑TLR2, functional recovery, GFAP, 5-HT, BMS score, motor function, and neuron survival; ↓CSPGs deposition, p-PI3K/PI3K, and NF-κB; ↓p-PI3K/PI3K and NF-κB | [92] |
Primary SCDEs | _____ | SCI | in vivo: SCI induced in SD rats in vitro: H2O2-induced injury in PC12 cells | 250 µL (0.1 µg/µL) in DPBS via tail vein injection, three times a week for 4 weeks | ↑Autophagy, motor function, myelinated areas, NeuN, ChAT, LC3-1/2 and Beclin-1, P62; ↓Apoptosis, %cavity size and EGFR; ↑Neuronal survival, LC3-1/2, Beclin-1 and P62; ↓Apoptosis, EGFR, p-Akt, and p-mTOR | [93] |
HUSC | ANGPTL3 | SCI | in vivo: SCI induced in mice in vitro: HUVECs | 200 μg in 200 μL of PBS via local intrathecal injection 200 μg | ↑Spinal cord regeneration, locomotor function, BMS scores, sensory improvement, MEP amplitudes, angiogenesis, vessel volume fraction, vascular segment and bifurcation numbers; ↓Latent period and lesion cavities area; ↑Proliferation rate, cell migration, tube formation, angiogenic activities, p-Akt, and p-PI3K | [94] |
hUC-MSCs | miR-199a-3p/145-5p | SCI | in vivo: SCI induced in SD rats in vitro: LPS-induced injury in PC12 cells | 20 μg/mL | ↑TrkA, locomotor function, and BBB score; ↓Lesion size, inflammation, and apoptotic cells ↑Cell viability, NF-H, β-tubulin-III, Neu-N, p-Akt, p-Erk, neurite outgrowth, and TrkA; ↓Cblb and Cbl expression; | [95] |
PMs | _____ | SCI | in vivo: SCI induced in SD rats in vitro: BV2 cells cultured in DMEM culture medium | 20 and 200 μg/mL via tail vein injection 20 and 200 μg/mL | ↑BBB score, inclined plate angle, Nissl-positive cells, IL-4, IL-10, and IL-13; ↓Tissue damage, IL-1β, IL-6, and TNF-α; ↑IL-10, CD206, CD163, Arg-1, LC3-II/Ⅰ, and Beclin-1; ↓p62, mTOR, and Akt protein level; | [96] |
Primary microglia | Resveratrol | SCI | in vivo: SCI induced in SD rats in vitro: Mechanical injury model in primary spinal cord neurons | 0.2 mL of PBS suspension of 40 µM for 14 days | ↑Muscle tension, foot functional movements, BBB scores, motor function, neuron natural morphology and number, LC3B-positive cells, Beclin-1, and p-PI3K; ↓TUNEL-positive neurons, cleaved caspase-3, and apoptosis; | [97] |
Pericytes | _____ | SCI | in vivo: SCI induced in ICR mice in vitro: SCMECs hypoxic model | 20 µg in 0.3 mL PBS via tail vein injection 20 µg/mL | ↑Locomotor function, complete tissue structure, myelin sheath, Nissl body morphology and number, blood flow, Bcl-2, local microvascular disturbances, mean flux, and claudin-5; ↓Inflammatory cell infiltration, TUNEL-positive cells, Bax, HIF-1α, BSCB disruption, edema formation, MMP-2, and AQP4; ↑ZO-1 and p-Akt; ↓PTEN; | [98] |
ECFCs | _____ | TBI | in vivo: TBI induced in male C57BL/6 mice in vitro: RBMEC hypoxia injury model | 4×106 cell equivalents via the tail vein at 2 h after TBI,5 and 10 μg/mL | ↑Neurological functional recovery, TJ, p-Akt, CLN5, occludin, and ZO-1; ↓Brain edema, PTEN, MMP-9, BBB permeability, EB dye extravasation, and TJ degradation | [101] |
Microglia | miR-124-3p | TBI | in vivo: (r)TBI male C57BL/6 mouse model in vitro: Scratch injury model in pure cortical neurons | 30 μg via tail vein, 3 × 108 exosomes | ↑Neurologic outcomes, neurite outgrowth and IL-10; ↓PDE4B, IL-1β, IL-6, TNF-α, mTOR signaling, neuronal inflammation, PDE4B, p-4E-BP1, and p-P70S6K; | [102] |
Human ADSC | _____ | TBI | in vivo: Weight-drop-induced TBI in male SD rats in vitro: LPS-induced inflammatory model | 20 μg total protein per rat, 2.0 × 1010 particles/mL, intracerebroventricular injection | ↑Functional recovery, neurogenesis, M1 to M2 microglial polarization, IGF1, arginase1, CD206 and IL-10; ↓Neuroinflammation, neuronal apoptosis, hippocampal neurogenesis, CD68+ activated microglia/macrophages, mNSS score, TNF-α, iNOS, IL-1α, IL-1β, IL-6, MCP-1, CCL2, CCL3, CCL5, morphological transformation, p-P38, p-IKKαβ, p-IKBα, p-P68, NF-κB, and P38/MAPK activation | [103] |
Source of Exosomes | Cargo or Intermediate Molecule | Disease | Method (In Vitro/In Vivo) | Dose/Route of Administration | Mechanism of Actions and Outcomes | References |
---|---|---|---|---|---|---|
ADSC | _____ | ALS | in vitro: H2O2-induced injury in NSC-34 (G93A) cells | 0.2 µg/mL, corresponding to 6–8 × 105 particles/mL | ↑Phospho-Akt, SOD1 gene, Bcl-2 α, and cell viability; ↓Cleaved caspase 3, Bax, and apoptosis; | [108] |
Fibroblast | _____ | CNS injury | in vitro: Cultured adult rat DRGs and RGCs | 50 ng/mL | ↑Cell survival, neurite growth, axonal growth, and pS6K; ↓CSPG and Wnt10b; | [109] |
Fibroblast | miR-673-5p | Peripheral neuron myelinati on | in vivo: One-day-old newborn rats in vitro: Schwann cells | 5 nmol/rat every 2 days via hypodermic injection | ↑Myelin gene expression, mTORC1, SREBP2, Hmgcr, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, diacyl glycerol, cholesterol, myelin sheath, myelinated axons, and myelin lamellae; ↓Tsc2 expression; | [110] |
MSCs | miR-17-92 | Axonal growth | in vitro: Primary cortical neurons under CSPG conditions | 3 × 108/300 µL and 3 × 109/300 µL | ↑Axonal growth, distal axons length, p-mTOR, and p-GSK-3β; ↓PTEN; | [111] |
ADSCs | _____ | Neural injury | in vitro: LPS-induced injury in SH-SY5Y and BV-2 cells | 50 μg/mL | ↑Cell viability; ↓Neuroinflammation, microglia cells, TNF-α, IL-1β, IL-6, COX-2, iNOS, cytotoxicity, p-P38, p-P65, p-ERK, and p-JNK; | [112] |
hAMS | _____ | Neural injury | in vitro: Neural injury induced by glutamate in PC12 cells | 100 ng/mL | ↑Cell survival and PI3K/Akt signaling activating; | [113] |
MSCs | _____ | ONC injury | in vivo: ONC-induced injury in SD rats | 3 × 109/5 μL, intravitreal injection | ↑RGCs survival, IL-10, Bcl-2, and p-Akt; ↓IL-1β, IL-6, IL-8, MCP-1, Bax, TNF-α, cleaved caspase-3, and apoptosis; | [114] |
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Iranpanah, A.; Kooshki, L.; Moradi, S.Z.; Saso, L.; Fakhri, S.; Khan, H. The Exosome-Mediated PI3K/Akt/mTOR Signaling Pathway in Neurological Diseases. Pharmaceutics 2023, 15, 1006. https://doi.org/10.3390/pharmaceutics15031006
Iranpanah A, Kooshki L, Moradi SZ, Saso L, Fakhri S, Khan H. The Exosome-Mediated PI3K/Akt/mTOR Signaling Pathway in Neurological Diseases. Pharmaceutics. 2023; 15(3):1006. https://doi.org/10.3390/pharmaceutics15031006
Chicago/Turabian StyleIranpanah, Amin, Leila Kooshki, Seyed Zachariah Moradi, Luciano Saso, Sajad Fakhri, and Haroon Khan. 2023. "The Exosome-Mediated PI3K/Akt/mTOR Signaling Pathway in Neurological Diseases" Pharmaceutics 15, no. 3: 1006. https://doi.org/10.3390/pharmaceutics15031006
APA StyleIranpanah, A., Kooshki, L., Moradi, S. Z., Saso, L., Fakhri, S., & Khan, H. (2023). The Exosome-Mediated PI3K/Akt/mTOR Signaling Pathway in Neurological Diseases. Pharmaceutics, 15(3), 1006. https://doi.org/10.3390/pharmaceutics15031006