Small but Mighty—Exosomes, Novel Intercellular Messengers in Neurodegeneration
Abstract
Simple Summary
Abstract
1. Introduction and Historical Perspective
2. Current Methods for Exosome Isolation
3. Role of Exosomes in the Central Nervous System (CNS)
Exosome Cell Source | Mode of Exosome Release | Synopsis of Function |
---|---|---|
Neuron | Calcium influx, glutamate-mediated synaptic activity regulates exosome release [49,115,117] |
|
Astrocyte | ATP released at synapses triggers exosome release Ultrasound induces a 5-fold increase in the exosome release by human astrocytes |
|
Oligodendrocytes (Olig) | Glutamate exposure activates NMDA and AMPA receptors resulting in an increase in intracellular calcium that in turn stimulates exosome release [138] | |
Microglia | Release of exosomes is triggered by ATP which is released at synapses as a co-transmitter and activates glial purinergic receptors Binding of serotonin to microglial 5-HT receptors increases intracellular Ca2+ levels that in turn stimulate exosome release [112] |
|
4. Role of Exosomes in Neurodegenerative Diseases
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Principle of the Method | Method | Methodology/Procedure | Application |
---|---|---|---|
Size and density based | Differential centrifugation (ultracentrifugation method) | Involves successive centrifugation steps with an increase in centrifugation forces and durations to separate small particles from large particles; reliable method but cumbersome [10] | Biological fluids, cell culture medium, RNA-seq and proteomic analyses |
Size and density based | Isopycnic or gradient centrifugation using:
| Involves density based separation of exosomes; exosomes have a density between 1.13 and 1.19 g mL−1; pure preparation but low yield [67,68] | Exosome preparation with relatively higher purity and can be used for exosomal RNAs and proteins studies; clinical-grade purified exosomes |
Size based | Microfiltration Ultrafiltration | Involves sequential filtration through “low protein” binding membranes with decreasing pore size, thereby excluding particles bigger than exosomes [69]; ultrafiltration involves the use of amicon filters [70]; membrane clogging and inability to exclude small particles from exosomes | Low-density biofluids such as urine and culture medium |
Size based | Size-exclusion chromatography using porous polymer beads or resin such as Sephacryl S-1000, Sepharose 2B, and Sepharose CL-2B | Involves loading of samples on to the resin packed column and sequential elution of particles as they traverse through the resin. Larger particles are eluted as flow through and small particles are eluted by passing buffer through the column [71]. Rapid and reproducible method, does not affect exosome integrity. A small fraction of high-density lipoprotein cholesterol and proteins co-elute with exosomes | Best for dilute biofluids, tissue culture medium, and tissue exosomes |
Size based | Hydrostatic filtration dialysis | Involves dialyzing out molecules through dialysis membrane with 1000 kDa cutoff size and recovery of exosomes by centrifugation [72] | Best for dilute biofluids and long-term storage of biofluids for exosome studies at a later date |
Precipitation or aggregation based | PEG 6000 | Involves precipitation of exosomes by addition of PEG 6000 (8–9% final concentration) to the sample; variable amounts of contaminants such as proteins, protein complexes, lipoproteins, and nucleoproteins in exosome preparations [73] | Allows exosome isolation from dilute samples and processing of several samples simultaneously |
Precipitation based | PEG 35,000 plus protamine | Involves precipitation of exosomes using positively charged protamine (0.25 mg/mL) in the presence of PEG 35,000 [74] | Best for plasma, saliva, and culture medium. For exosomal RNA analysis |
Precipitation based | Sodium acetate | Involves addition of acetate to 0.1M pH ~4.75 to neutralize surface charge and salt-out exosomes; depends on both pH and salt concentration, rapid method [75]; may affect surface properties of exosomes | Best for culture medium or dilute biological samples; may have applied value for quick exosome isolation |
Precipitation based | Organic liquid (PROSPR) | Involves precipitation of plasma proteins by addition of cold acetone (−20 °C) four times the volume of plasma; separation of precipitated proteins and recovery of exosomes require additional methods such as ultrafiltration or ultracentrifugation [76]; acetone may coagulate membrane proteins and dissolve exosome membrane lipids | Best for small volume samples such as plasma |
Precipitation based | PEG + dextran | Involves repeated extraction using two-phase system consisting of 4.5% PEG 25,000~45,000 and 1.5% dextran (450,000 to ~650,000 molecular weight); removes >95% of the serum proteins [77]; difficult to recover exosomes from dextran | Best for plasma and culture medium; used for RNA isolation |
Affinity based | Antibodies such as Tim4, annexin, EpCAM, CD63, and heat shock proteins conjugated to paramagnetic beads, porous monolithic silica microtips, plastic plates, cellulose filters, membrane affinity filters, agarose beads, and microfluidic devices | Involves sample incubation with a surface (e.g., paramagnetic beads) conjugated to antibody [78,79], exosome elution by incubation with IgG and exosome concentration by ultracentrifugation; highly specific but difficult to elute exosomes [79]; purifies a sub-population of exosomes that can be beneficial when trying to detect exosomes from specific parent cells in biological fluids | Isolation of exosomes with specific exosomal markers, e.g., cancer-specific proteins; larger sample volumes can be processed |
Affinity based | Lectin Heparin | Involves incubation of samples with lectin that binds to glycoproteins on exosome surface or heparin that binds to heparan sulfate proteoglycans on exosome surface [80,81] | Rapid, allows isolation of exosome for RNA analysis; may be valuable for medical clinical diagnosis |
Physiochemical and biochemical such as hydrodynamic and dielectrophoretic properties based | Microfluidic devices
| Involves flow of sample through a small device; exosome purification depends upon their hydrodynamic, dielectrophoretic, and biochemical properties [82,83] | Rapid, microscale isolation for medical clinical diagnosis |
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Kumari, M.; Anji, A. Small but Mighty—Exosomes, Novel Intercellular Messengers in Neurodegeneration. Biology 2022, 11, 413. https://doi.org/10.3390/biology11030413
Kumari M, Anji A. Small but Mighty—Exosomes, Novel Intercellular Messengers in Neurodegeneration. Biology. 2022; 11(3):413. https://doi.org/10.3390/biology11030413
Chicago/Turabian StyleKumari, Meena, and Antje Anji. 2022. "Small but Mighty—Exosomes, Novel Intercellular Messengers in Neurodegeneration" Biology 11, no. 3: 413. https://doi.org/10.3390/biology11030413
APA StyleKumari, M., & Anji, A. (2022). Small but Mighty—Exosomes, Novel Intercellular Messengers in Neurodegeneration. Biology, 11(3), 413. https://doi.org/10.3390/biology11030413