Extracellular vesicles and a novel form of communication in the brain

Frontiers in Neuroscience

Volumn 10, Issue MAR, 2016, Pages

  Basso, Manuela ^a   Bonetto, Valentina ^b  

^a UNIVERSITY OF TRENTO   (Italy)

^b MARIO NEGRI INSTITUTE FOR PHARMACOLOGICAL RESEARCH   (Italy)

Author keywords

Cargo; Exosomes; Microvesicles; Nanotechnologies; Neurodegeneration

Indexed keywords

CARRIER PROTEIN; COPPER ZINC SUPEROXIDE DISMUTASE; MUTANT PROTEIN; NUCLEIC ACID; PRION PROTEIN; PROTEIN;

BIOGENESIS; BRAIN; BRAIN NERVE CELL; CELL ACTIVATION; CELL COMMUNICATION; CELL INTERACTION; DEGENERATIVE DISEASE; EXOSOME; GLIA CELL; HUMAN; LIPID TRANSPORT; MICROGLIA; NERVE FUNCTION; NONHUMAN; NUCLEOTIDE TRANSPORT; PRION DISEASE; PROTEIN TRANSPORT; PROTEOMICS; REGULATORY MECHANISM; REVIEW;

EID: 84964336988     PISSN: 16624548     EISSN: 1662453X     Source Type: Journal    
DOI: 10.3389/fnins.2016.00127     Document Type: Review

References (124)

1. Alural, B., Duran, G. A., Tufekci, K. U., Allmer, J., Onkal, Z., Tunali, D., et al. (2014). EPO mediates neurotrophic, neuroprotective, anti-oxidant, and anti-apoptotic effects via downregulation of miR-451 and miR-885-5p in SH-SY5Y neuron-Like cells. Front. Immunol. 5:475. doi: 10.3389/fimmu.2014.00475
2. Alvarez-Erviti, L., Seow, Y., Schapira, A. H., Gardiner, C., Sargent, I. L., Wood, M. J., et al. (2011a). Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission. Neurobiol. Dis. 42, 360-367. doi: 10.1016/j.nbd.2011.01.029
3. Alvarez-Erviti, L., Seow, Y., Yin, H., Betts, C., Lakhal, S., and Wood, M. J. (2011b). Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat. Biotechnol. 29, 341-345. doi: 10.1038/nbt.1807
4. Antonucci, F., Turola, E., Riganti, L., Caleo, M., Gabrielli, M., Perrotta, C., et al. (2012). Microvesicles released from microglia stimulate synaptic activity via enhanced sphingolipid metabolism. EMBO J. 31, 1231-1240. doi: 10.1038/emboj.2011.489
5. Asai, H., Ikezu, S., Tsunoda, S., Medalla, M., Luebke, J., Haydar, T., et al. (2015). Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat. Neurosci. 18, 1584-1593. doi: 10.1038/nn.4132
6. Baietti, M. F., Zhang, Z., Mortier, E., Melchior, A., Degeest, G., Geeraerts, A., et al. (2012). Syndecan-syntenin-ALIX regulates the biogenesis of exosomes. Nat. Cell Biol. 14, 677-685. doi: 10.1038/ncb2502
7. Basso, M., Pozzi, S., Tortarolo, M., Fiordaliso, F., Bisighini, C., Pasetto, L., et al. (2013). Mutant copper-zinc superoxide dismutase (SOD1) induces protein secretion pathway alterations and exosome release in astrocytes: implications for disease spreading and motor neuron pathology in amyotrophic lateral sclerosis. J. Biol. Chem. 288, 15699-15711. doi: 10.1074/jbc. M112.425066
8. Beck, M., Schmidt, A., Malmstroem, J., Claassen, M., Ori, A., Szymborska, A., et al. (2011). The quantitative proteome of a human cell line. Mol. Syst. Biol. 7, 549. doi: 10.1038/msb.2011.82
9. Bellingham, S. A., Coleman, B. M., and Hill, A. F. (2012). Small RNA deep sequencing reveals a distinct miRNA signature released in exosomes from prion-infected neuronal cells. Nucleic Acids Res. 40, 10937-10949. doi: 10.1093/nar/gks832
10. Bendotti, C., Marino, M., Cheroni, C., Fontana, E., Crippa, V., Poletti, A., et al. (2012). Dysfunction of constitutive and inducible ubiquitin-proteasome system in amyotrophic lateral sclerosis: implication for protein aggregation and immune response. Prog. Neurobiol. 97, 101-126. doi: 10.1016/j.pneurobio.2011.10.001
11. Bianco, F., Pravettoni, E., Colombo, A., Schenk, U., Moller, T., Matteoli, M., et al. (2005). Astrocyte-derived ATP induces vesicle shedding and IL-1 beta release from microglia. J. Immunol. 174, 7268-7277. doi: 10.4049/jimmunol.174.11.7268
12. Binotti, B., Jahn, R., and Chua, J. J. (2016). Functions of rab proteins at presynaptic sites. Cells 5:E7. doi: 10.3390/cells5010007
13. Boillee, S., Yamanaka, K., Lobsiger, C. S., Copeland, N. G., Jenkins, N. A., Kassiotis, G., et al. (2006). Onset and progression in inherited ALS determined by motor neurons and microglia. Science 312, 1389-1392. doi: 10.1126/science.1123511
14. Carson, J. H., and Barbarese, E. (2005). Systems analysis of RNA trafficking in neural cells. Biol. Cell 97, 51-62. doi: 10.1042/BC20040083
15. Chan, C. C., Scoggin, S., Wang, D., Cherry, S., Dembo, T., Greenberg, B., et al. (2011). Systematic discovery of Rab GTPases with synaptic functions in Drosophila. Curr. Biol. 21, 1704-1715. doi: 10.1016/j.cub.2011.08.058
16. Chang, C., Lang, H., Geng, N., Wang, J., Li, N., and Wang, X. (2013). Exosomes of BV-2 cells induced by alpha-synuclein: important mediator of neurodegeneration in PD. Neurosci. Lett. 548, 190-195. doi: 10.1016/j.neulet.2013.06.009
17. Chen, S., Zhang, X., Song, L., and Le, W. (2012). Autophagy dysregulation in amyotrophic lateral sclerosis. Brain Pathol. 22, 110-116. doi: 10.1111/j.1750-3639.2011.00546.x
18. Chen, X., Liang, H., Zhang, J., Zen, K., and Zhang, C. Y. (2012). Horizontal transfer of microRNAs: molecular mechanisms and clinical applications. Protein Cell 3, 28-37. doi: 10.1007/s13238-012-2003-z
19. Chevallier, J., Koop, C., Srivastava, A., Petrie, R. J., Lamarche-Vane, N., and Presley, J. F. (2009). Rab35 regulates neurite outgrowth and cell shape. FEBS Lett. 583, 1096-1101. doi: 10.1016/j.febslet.2009.03.012
20. Chevillet, J. R., Kang, Q., Ruf, I. K., Briggs, H. A., Vojtech, L. N., Hughes, S. M., et al. (2014). Quantitative and stoichiometric analysis of the microRNA content of exosomes. Proc. Natl. Acad. Sci. U.S.A. 111, 14888-14893. doi: 10.1073/pnas.1408301111
21. Chiasserini, D., Van Weering, J. R., Piersma, S. R., Pham, T. V., Malekzadeh, A., Teunissen, C. E., et al. (2014). Proteomic analysis of cerebrospinal fluid extracellular vesicles: a comprehensive dataset. J. Proteomics 106, 191-204. doi: 10.1016/j.jprot.2014.04.028
22. Chivet, M., Javalet, C., Hemming, F., Pernet-Gallay, K., Laulagnier, K., Fraboulet, S., et al. (2013). Exosomes as a novel way of interneuronal communication. Biochem. Soc. Trans. 41, 241-244. doi: 10.1042/BST20120266
23. Chutna, O., Goncalves, S., Villar-Pique, A., Guerreiro, P., Marijanovic, Z., Mendes, T., et al. (2014). The small GTPase Rab11 co-localizes with alpha-synuclein in intracellular inclusions and modulates its aggregation, secretion and toxicity. Hum. Mol. Genet. 23, 6732-6745. doi: 10.1093/hmg/ddu391
24. Cocucci, E., and Meldolesi, J. (2015). Ectosomes and exosomes: shedding the confusion between extracellular vesicles. Trends Cell Biol. 25, 364-372. doi: 10.1016/j.tcb.2015.01.004
25. Cocucci, E., Racchetti, G., and Meldolesi, J. (2009). Shedding microvesicles: artefacts no more. Trends Cell Biol. 19, 43-51. doi: 10.1016/j.tcb.2008.11.003
26. Coleman, B. M., and Hill, A. F. (2015). Extracellular vesicles-Their role in the packaging and spread of misfolded proteins associated with neurodegenerative diseases. Semin. Cell Dev. Biol. 40, 89-96. doi: 10.1016/j.semcdb.2015.02.007
27. Colombo, E., Borgiani, B., Verderio, C., and Furlan, R. (2012). Microvesicles: novel biomarkers for neurological disorders. Front. Physiol. 3:63. doi: 10.3389/fphys.2012.00063
28. Colombo, M., Moita, C., Van Niel, G., Kowal, J., Vigneron, J., Benaroch, P., et al. (2013). Analysis of ESCRT functions in exosome biogenesis, composition and secretion highlights the heterogeneity of extracellular vesicles. J. Cell Sci. 126, 5553-5565. doi: 10.1242/jcs.128868
29. Colombo, M., Raposo, G., and Théry, C. (2014). Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu. Rev. Cell Dev. Biol. 30, 255-289. doi: 10.1146/annurev-cellbio-101512-122326
30. Cooper, J. M., Wiklander, P. B., Nordin, J. Z., Al-Shawi, R., Wood, M. J., Vithlani, M., et al. (2014). Systemic exosomal siRNA delivery reduced alpha-synuclein aggregates in brains of transgenic mice. Movem. Disord. 29, 1476-1485. doi: 10.1002/mds.25978
31. Danzer, K. M., Kranich, L. R., Ruf, W. P., Cagsal-Getkin, O., Winslow, A. R., Zhu, L., et al. (2012). Exosomal cell-to-cell transmission of alpha synuclein oligomers. Mol. Neurodegener. 7:42. doi: 10.1186/1750-1326-7-42
32. Ding, X., Ma, M., Teng, J., Teng, R. K., Zhou, S., Yin, J., et al. (2015). Exposure to ALS-FTD-CSF generates TDP-43 aggregates in glioblastoma cells through exosomes and TNTs-like structure. Oncotarget 6, 24178-24191. doi: 10.18632/oncotarget.4680
33. Dinkins, M. B., Dasgupta, S., Wang, G., Zhu, G., and Bieberich, E. (2014). Exosome reduction in vivo is associated with lower amyloid plaque load in the 5XFAD mouse model of Alzheimer's disease. Neurobiol. Aging 35, 1792-1800. doi: 10.1016/j.neurobiolaging.2014.02.012
34. El-Andaloussi, S., Lee, Y., Lakhal-Littleton, S., Li, J., Seow, Y., Gardiner, C., et al. (2012). Exosome-mediated delivery of siRNA in vitro and in vivo. Nat. Protoc. 7, 2112-2126. doi: 10.1038/nprot.2012.131
35. Emmanouilidou, E., Melachroinou, K., Roumeliotis, T., Garbis, S. D., Ntzouni, M., Margaritis, L. H., et al. (2010). Cell-produced alpha-synuclein is secreted in a calcium-dependent manner by exosomes and impacts neuronal survival. J. Neurosci. 30, 6838-6851. doi: 10.1523/JNEUROSCI.5699-09.2010
36. Etoh, K., and Fukuda, M. (2015). Structure-function analyses of the small GTPase Rab35 and its effector protein centaurin-beta2/ACAP2 during neurite outgrowth of PC12 cells. J. Biol. Chem. 290, 9064-9074. doi: 10.1074/jbc. M114.611301
37. Fang, Y., Wu, N., Gan, X., Yan, W., Morrell, J. C., and Gould, S. J. (2007). Higher-order oligomerization targets plasma membrane proteins and HIV gag to exosomes. PLoS Biol. 5:e158. doi: 10.1371/journal.pbio.0050158
38. Faure, J., Lachenal, G., Court, M., Hirrlinger, J., Chatellard-Causse, C., Blot, B., et al. (2006). Exosomes are released by cultured cortical neurones. Mol. Cell. Neurosci. 31, 642-648. doi: 10.1016/j.mcn.2005.12.003
39. Fevrier, B., Vilette, D., Archer, F., Loew, D., Faigle, W., Vidal, M., et al. (2004). Cells release prions in association with exosomes. Proc. Natl. Acad. Sci. U.S.A. 101, 9683-9688. doi: 10.1073/pnas.0308413101
40. Fiandaca, M. S., Kapogiannis, D., Mapstone, M., Boxer, A., Eitan, E., Schwartz, J. B., et al. (2015). Identification of preclinical Alzheimer's disease by a profile of pathogenic proteins in neurally derived blood exosomes: a case-control study. Alzheimer's Dement. 11:600-7.e1. doi: 10.1016/j.jalz.2014.06.008
41. Frey, B., and Gaipl, U. S. (2011). The immune functions of phosphatidylserine in membranes of dying cells and microvesicles. Semin. Immunopathol. 33, 497-516. doi: 10.1007/s00281-010-0228-6
42. Fröhlich, D., Kuo, W. P., Frühbeis, C., Sun, J. J., Zehendner, C. M., Luhmann, H. J., et al. (2014). Multifaceted effects of oligodendroglial exosomes on neurons: impact on neuronal firing rate, signal transduction and gene regulation. Philos. Trans. R. Soc. Lond. Ser. B Biol. Sci. 369:20130510. doi: 10.1098/rstb.2013.0510
43. Fruhbeis, C., Frohlich, D., Kuo, W. P., Amphornrat, J., Thilemann, S., Saab, A. S., et al. (2013). Neurotransmitter-triggered transfer of exosomes mediates oligodendrocyte-neuron communication. PLoS Biol. 11:e1001604. doi: 10.1371/journal.pbio.1001604
44. Gabrielli, M., Battista, N., Riganti, L., Prada, I., Antonucci, F., Cantone, L., et al. (2015). Active endocannabinoids are secreted on extracellular membrane vesicles. EMBO Rep. 16, 213-220. doi: 10.15252/embr.201439668
45. Gan, X., and Gould, S. J. (2011). Identification of an inhibitory budding signal that blocks the release of HIV particles and exosome/microvesicle proteins. Mol. Biol. Cell 22, 817-830. doi: 10.1091/mbc. E10-07-0625
46. Garden, G. A., and La Spada, A. R. (2012). Intercellular (mis)communication in neurodegenerative disease. Neuron 73, 886-901. doi: 10.1016/j.neuron.2012.02.017
47. Ghidoni, R., Benussi, L., and Binetti, G. (2008). Exosomes: the Trojan horses of neurodegeneration. Med. Hypotheses 70, 1226-1227. doi: 10.1016/j.mehy.2007.12.003
48. Goetzl, E. J., Boxer, A., Schwartz, J. B., Abner, E. L., Petersen, R. C., Miller, B. L., et al. (2015). Altered lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease. Neurology 85, 40-47. doi: 10.1212/WNL.0000000000001702
49. Goldie, B. J., Dun, M. D., Lin, M., Smith, N. D., Verrills, N. M., Dayas, C. V., et al. (2014). Activity-associated miRNA are packaged in Map1b-enriched exosomes released from depolarized neurons. Nucleic Acids Res. 42, 9195-9208. doi: 10.1093/nar/gku594
50. Gomes, C., Keller, S., Altevogt, P., and Costa, J. (2007). Evidence for secretion of Cu, Zn superoxide dismutase via exosomes from a cell model of amyotrophic lateral sclerosis. Neurosci. Lett. 428, 43-46. doi: 10.1016/j.neulet.2007.09.024
51. Gosselin, R. D., Meylan, P., and Decosterd, I. (2013). Extracellular microvesicles from astrocytes contain functional glutamate transporters: regulation by protein kinase C and cell activation. Front. Cell. Neurosci. 7:251. doi: 10.3389/fncel.2013.00251
52. Grad, L. I., Yerbury, J. J., Turner, B. J., Guest, W. C., Pokrishevsky, E., O'neill, M. A., et al. (2014). Intercellular propagated misfolding of wild-type Cu/Zn superoxide dismutase occurs via exosome-dependent and -independent mechanisms. Proc. Natl. Acad. Sci. U.S.A. 111, 3620-3625. doi: 10.1073/pnas.1312245111
53. Gross, J. C., Chaudhary, V., Bartscherer, K., and Boutros, M. (2012). Active Wnt proteins are secreted on exosomes. Nat. Cell Biol. 14, 1036-1045. doi: 10.1038/ncb2574
54. Gu, X., Li, C., Wei, W., Lo, V., Gong, S., Li, S. H., et al. (2005). Pathological cell-cell interactions elicited by a neuropathogenic form of mutant Huntingtin contribute to cortical pathogenesis in HD mice. Neuron 46, 433-444. doi: 10.1016/j.neuron.2005.03.025
55. Guduric-Fuchs, J., O'connor, A., Camp, B., O'neill, C. L., Medina, R. J., and Simpson, D. A. (2012). Selective extracellular vesicle-mediated export of an overlapping set of microRNAs from multiple cell types. BMC Genomics 13:357. doi: 10.1186/1471-2164-13-357
56. Harrington, M. G., Fonteh, A. N., Oborina, E., Liao, P., Cowan, R. P., Mccomb, G., et al. (2009). The morphology and biochemistry of nanostructures provide evidence for synthesis and signaling functions in human cerebrospinal fluid. Cerebrospinal Fluid Res. 6:10. doi: 10.1186/1743-8454-6-10
57. Ilieva, H., Polymenidou, M., and Cleveland, D. W. (2009). Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond. J. Cell Biol. 187, 761-772. doi: 10.1083/jcb.200908164
58. Janas, T., Janas, M. M., and Sapon, K. (2015). Mechanisms of RNA loading into exosomes. FEBS Lett. 589, 1391-1398. doi: 10.1016/j.febslet.2015.04.036
59. Janas, T., and Yarus, M. (2006). Specific RNA binding to ordered phospholipid bilayers. Nucleic Acids Res. 34, 2128-2136. doi: 10.1093/nar/gkl220
60. Jeppesen, D. K., Hvam, M. L., Primdahl-Bengtson, B., Boysen, A. T., Whitehead, B., Dyrskjot, L., et al. (2014). Comparative analysis of discrete exosome fractions obtained by differential centrifugation. J. Extracell. Vesicl. 3:25011. doi: 10.3402/jev.v3.25011
61. Johnson, J. O., Mandrioli, J., Benatar, M., Abramzon, Y., Van Deerlin, V. M., Trojanowski, J. Q., et al. (2010). Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 68, 857-864. doi: 10.1016/j.neuron.2010.11.036
62. Joshi, P., Turola, E., Ruiz, A., Bergami, A., Libera, D. D., Benussi, L., et al. (2014). Microglia convert aggregated amyloid-beta into neurotoxic forms through the shedding of microvesicles. Cell Death Differ. 21, 582-593. doi: 10.1038/cdd.2013.180
63. Kalra, H., Simpson, R. J., Ji, H., Aikawa, E., Altevogt, P., Askenase, P., et al. (2012). Vesiclepedia: a compendium for extracellular vesicles with continuous community annotation. PLoS Biol. 10:e1001450. doi: 10.1371/journal.pbio.1001450
64. Kanada, M., Bachmann, M. H., Hardy, J. W., Frimannson, D. O., Bronsart, L., Wang, A., et al. (2015). Differential fates of biomolecules delivered to target cells via extracellular vesicles. Proc. Natl. Acad. Sci. U.S.A. 112, E1433-E1442. doi: 10.1073/pnas.1418401112
65. Kapuralin, K., Curlin, M., Mitrecic, D., Kosi, N., Schwarzer, C., Glavan, G., et al. (2015). STAM2, a member of the endosome-associated complex ESCRT-0 is highly expressed in neurons. Mol. Cell. Neurosci. 67, 104-115. doi: 10.1016/j.mcn.2015.06.009
66. Keerthikumar, S., Chisanga, D., Ariyaratne, D., Al Saffar, H., Anand, S., Zhao, K., et al. (2015a). ExoCarta: a web-based compendium of exosomal cargo. J. Mol. Biol. 428, 688-692. doi: 10.1016/j.jmb.2015.09.019
67. Keerthikumar, S., Gangoda, L., Liem, M., Fonseka, P., Atukorala, I., Ozcitti, C., et al. (2015b). Proteogenomic analysis reveals exosomes are more oncogenic than ectosomes. Oncotarget 6, 15375-15396. doi: 10.18632/oncotarget.3801
68. Kim, D. K., Lee, J., Kim, S. R., Choi, D. S., Yoon, Y. J., Kim, J. H., et al. (2015). EVpedia: a community web portal for extracellular vesicles research. Bioinformatics 31, 933-939. doi: 10.1093/bioinformatics/btu741
69. Kim, H. J., Kim, N. C., Wang, Y. D., Scarborough, E. A., Moore, J., Diaz, Z., et al. (2013). Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495, 467-473. doi: 10.1038/nature11922
70. Kim, K., Lee, S. G., Kegelman, T. P., Su, Z. Z., Das, S. K., Dash, R., et al. (2011). Role of excitatory amino acid transporter-2 (EAAT2) and glutamate in neurodegeneration: opportunities for developing novel therapeutics. J. Cell. Physiol. 226, 2484-2493. doi: 10.1002/jcp.22609
71. Kobayashi, H., Etoh, K., and Fukuda, M. (2014). Rab35 is translocated from Arf6-positive perinuclear recycling endosomes to neurite tips during neurite outgrowth. Small GTPases 5, e29290. doi: 10.4161/sgtp.29290
72. Kobayashi, H., and Fukuda, M. (2012). Rab35 regulates Arf6 activity through centaurin-beta2 (ACAP2) during neurite outgrowth. J. Cell Sci. 125, 2235-2243. doi: 10.1242/jcs.098657
73. Kobayashi, H., and Fukuda, M. (2013). Rab35 establishes the EHD1-association site by coordinating two distinct effectors during neurite outgrowth. J. Cell Sci. 126, 2424-2435. doi: 10.1242/jcs.117846
74. Korkut, C., Li, Y., Koles, K., Brewer, C., Ashley, J., Yoshihara, M., et al. (2013). Regulation of postsynaptic retrograde signaling by presynaptic exosome release. Neuron 77, 1039-1046. doi: 10.1016/j.neuron.2013.01.013
75. Kramer-Albers, E. M., Bretz, N., Tenzer, S., Winterstein, C., Mobius, W., Berger, H., et al. (2007). Oligodendrocytes secrete exosomes containing major myelin and stress-protective proteins: Trophic support for axons? Proteomics. Clin. Appl. 1, 1446-1461. doi: 10.1002/prca.200700522
76. Lachenal, G., Pernet-Gallay, K., Chivet, M., Hemming, F. J., Belly, A., Bodon, G., et al. (2011). Release of exosomes from differentiated neurons and its regulation by synaptic glutamatergic activity. Mol. Cell. Neurosci. 46, 409-418. doi: 10.1016/j.mcn.2010.11.004
77. Lai, C. P., Mardini, O., Ericsson, M., Prabhakar, S., Maguire, C. A., Chen, J. W., et al. (2014a). Dynamic biodistribution of extracellular vesicles in vivo using a multimodal imaging reporter. ACS Nano 8, 483-494. doi: 10.1021/nn404945r
78. Lai, C. P., Tannous, B. A., and Breakefield, X. O. (2014b). Noninvasive in vivo monitoring of extracellular vesicles. Methods Mol. Biol. 1098, 249-258. doi: 10.1007/978-1-62703-718-1_19
79. Lauranzano, E., Pozzi, S., Pasetto, L., Stucchi, R., Massignan, T., Paolella, K., et al. (2015). Peptidylprolyl isomerase A governs TARDBP function and assembly in heterogeneous nuclear ribonucleoprotein complexes. Brain 138, 974-991. doi: 10.1093/brain/awv005
80. Lotvall, J., Hill, A. F., Hochberg, F., Buzas, E. I., Di Vizio, D., Gardiner, C., et al. (2014). Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles. J. Extracell. Vesicl. 3:26913. doi: 10.3402/jev.v3.26913
81. Lugli, G., Cohen, A. M., Bennett, D. A., Shah, R. C., Fields, C. J., Hernandez, A. G., et al. (2015). Plasma exosomal miRNAs in persons with and without Alzheimer Disease: altered expression and prospects for biomarkers. PLoS ONE 10:e0139233. doi: 10.1371/journal.pone.0139233
82. Maas, S. L., De Vrij, J., Van Der Vlist, E. J., Geragousian, B., Van Bloois, L., Mastrobattista, E., et al. (2015). Possibilities and limitations of current technologies for quantification of biological extracellular vesicles and synthetic mimics. J. Contr. Release. 200, 87-96. doi: 10.1016/j.jconrel.2014.12.041
83. Marimpietri, D., Petretto, A., Raffaghello, L., Pezzolo, A., Gagliani, C., Tacchetti, C., et al. (2013). Proteome profiling of neuroblastoma-derived exosomes reveal the expression of proteins potentially involved in tumor progression. PLoS ONE 8:e75054. doi: 10.1371/journal.pone.0075054
84. Mathivanan, S., and Simpson, R. J. (2009). ExoCarta: a compendium of exosomal proteins and RNA. Proteomics 9, 4997-5000. doi: 10.1002/pmic.200900351
85. Meissner, L., Gallozzi, M., Balbi, M., Schwarzmaier, S. M., Tiedt, S., Terpolilli, N. A., et al. (2015). Temporal profile of microRNA expression in contused cortex following traumatic brain injury in mice. J. Neurotrauma. doi: 10.1089/neu.2015.4077. [Epub ahead of print]
86. Morel, L., Regan, M., Higashimori, H., Ng, S. K., Esau, C., Vidensky, S., et al. (2013). Neuronal exosomal miRNA-dependent translational regulation of astroglial glutamate transporter GLT1. J. Biol. Chem. 288, 7105-7116. doi: 10.1074/jbc. M112.410944
87. Muralidharan-Chari, V., Clancy, J., Plou, C., Romao, M., Chavrier, P., Raposo, G., et al. (2009). ARF6-regulated shedding of tumor cell-derived plasma membrane microvesicles. Curr. Biol. 19, 1875-1885. doi: 10.1016/j.cub.2009.09.059
88. Nardo, G., Pozzi, S., Pignataro, M., Lauranzano, E., Spano, G., Garbelli, S., et al. (2011). Amyotrophic lateral sclerosis multiprotein biomarkers in peripheral blood mononuclear cells. PLoS ONE 6:e25545. doi: 10.1371/journal.pone.0025545
89. Nolte-'T Hoen, E. N., Van Der Vlist, E. J., Aalberts, M., Mertens, H. C., Bosch, B. J., Bartelink, W., et al. (2012). Quantitative and qualitative flow cytometric analysis of nanosized cell-derived membrane vesicles. Nanomedicine 8, 712-720. doi: 10.1016/j.nano.2011.09.006
90. Nonaka, T., Masuda-Suzukake, M., Arai, T., Hasegawa, Y., Akatsu, H., Obi, T., et al. (2013). Prion-like properties of pathological TDP-43 aggregates from diseased brains. Cell Rep. 4, 124-134. doi: 10.1016/j.celrep.2013.06.007
91. Ostrowski, M., Carmo, N. B., Krumeich, S., Fanget, I., Raposo, G., Savina, A., et al. (2010). Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat. Cell Biol. 12, 19-30. doi: 10.1038/ncb2000
92. Potolicchio, I., Carven, G. J., Xu, X., Stipp, C., Riese, R. J., Stern, L. J., et al. (2005). Proteomic analysis of microglia-derived exosomes: metabolic role of the aminopeptidase CD13 in neuropeptide catabolism. J. Immunol. 175, 2237-2243. doi: 10.4049/jimmunol.175.4.2237
93. Proia, P., Schiera, G., Mineo, M., Ingrassia, A. M., Santoro, G., Savettieri, G., et al. (2008). Astrocytes shed extracellular vesicles that contain fibroblast growth factor-2 and vascular endothelial growth factor. Int. J. Mol. Med. 21, 63-67. doi: 10.3892/ijmm.21.1.63
94. Rajendran, L., Honsho, M., Zahn, T. R., Keller, P., Geiger, K. D., Verkade, P., et al. (2006). Alzheimer's disease beta-amyloid peptides are released in association with exosomes. Proc. Natl. Acad. Sci. U.S.A. 103, 11172-11177. doi: 10.1073/pnas.0603838103
95. Ramachandran, S., and Palanisamy, V. (2012). Horizontal transfer of RNAs: exosomes as mediators of intercellular communication. Wiley Interdiscipl. Rev. RNA 3, 286-293. doi: 10.1002/wrna.115
96. Rao, P., Benito, E., and Fischer, A. (2013). MicroRNAs as biomarkers for CNS disease. Front. Mol. Neurosci. 6:39. doi: 10.3389/fnmol.2013.00039
97. Saman, S., Kim, W., Raya, M., Visnick, Y., Miro, S., Jackson, B., et al. (2012). Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease. J. Biol. Chem. 287, 3842-3849. doi: 10.1074/jbc. M111.277061
98. Savina, A., Fader, C. M., Damiani, M. T., and Colombo, M. I. (2005). Rab11 promotes docking and fusion of multivesicular bodies in a calcium-dependent manner. Traffic 6, 131-143. doi: 10.1111/j.1600-0854.2004.00257.x
99. Savina, A., Vidal, M., and Colombo, M. I. (2002). The exosome pathway in K562 cells is regulated by Rab11. J. Cell Sci. 115, 2505-2515
100. Sbai, O., Ould-Yahoui, A., Ferhat, L., Gueye, Y., Bernard, A., Charrat, E., et al. (2010). Differential vesicular distribution and trafficking of MMP-2, MMP-9, and their inhibitors in astrocytes. Glia 58, 344-366. doi: 10.1002/glia.20927
101. Schiera, G., Proia, P., Alberti, C., Mineo, M., Savettieri, G., and Di Liegro, I. (2007). Neurons produce FGF2 and VEGF and secrete them at least in part by shedding extracellular vesicles. J. Cell. Mol. Med. 11, 1384-1394. doi: 10.1111/j.1582-4934.2007.00100.x
102. Shi, M., Liu, C., Cook, T. J., Bullock, K. M., Zhao, Y., Ginghina, C., et al. (2014). Plasma exosomal alpha-synuclein is likely CNS-derived and increased in Parkinson's disease. Acta Neuropathol. 128, 639-650. doi: 10.1007/s00401-014-1314-y
103. Soo, C. Y., Song, Y., Zheng, Y., Campbell, E. C., Riches, A. C., Gunn-Moore, F., et al. (2012). Nanoparticle tracking analysis monitors microvesicle and exosome secretion from immune cells. Immunology 136, 192-197. doi: 10.1111/j.1365-2567.2012.03569.x
104. Stenmark, H. (2009). Rab GTPases as coordinators of vesicle traffic. Nat. Rev. Mol. Cell Biol. 10, 513-525. doi: 10.1038/nrm2728
105. Street, J. M., Barran, P. E., Mackay, C. L., Weidt, S., Balmforth, C., Walsh, T. S., et al. (2012). Identification and proteomic profiling of exosomes in human cerebrospinal fluid. J. Transl. Med. 10:5. doi: 10.1186/1479-5876-10-5
106. Tomlinson, P. R., Zheng, Y., Fischer, R., Heidasch, R., Gardiner, C., Evetts, S., et al. (2015). Identification of distinct circulating exosomes in Parkinson's disease. Ann. Clin. Trans. Neurol. 2, 353-361. doi: 10.1002/acn3.175
107. Trajkovic, K., Hsu, C., Chiantia, S., Rajendran, L., Wenzel, D., Wieland, F., et al. (2008). Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 319, 1244-1247. doi: 10.1126/science.1153124
108. Turola, E., Furlan, R., Bianco, F., Matteoli, M., and Verderio, C. (2012). Microglial microvesicle secretion and intercellular signaling. Front. Physiol. 3:149. doi: 10.3389/fphys.2012.00149
109. Valadi, H., Ekstrom, K., Bossios, A., Sjostrand, M., Lee, J. J., and Lotvall, J. O. (2007). Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell Biol. 9, 654-659. doi: 10.1038/ncb1596
110. Vella, L. J., Greenwood, D. L., Cappai, R., Scheerlinck, J. P., and Hill, A. F. (2008a). Enrichment of prion protein in exosomes derived from ovine cerebral spinal fluid. Vet. Immunol. Immunopathol. 124, 385-393. doi: 10.1016/j.vetimm.2008.04.002
111. Vella, L. J., Sharples, R. A., Lawson, V. A., Masters, C. L., Cappai, R., and Hill, A. F. (2007). Packaging of prions into exosomes is associated with a novel pathway of PrP processing. J. Pathol. 211, 582-590. doi: 10.1002/path.2145
112. Vella, L. J., Sharples, R. A., Nisbet, R. M., Cappai, R., and Hill, A. F. (2008b). The role of exosomes in the processing of proteins associated with neurodegenerative diseases. Eur. Biophys. J. 37, 323-332. doi: 10.1007/s00249-007-0246-z
113. Verderio, C., Muzio, L., Turola, E., Bergami, A., Novellino, L., Ruffini, F., et al. (2012). Myeloid microvesicles are a marker and therapeutic target for neuroinflammation. Ann. Neurol. 72, 610-624. doi: 10.1002/ana.23627
114. Vidal, M., Mangeat, P., and Hoekstra, D. (1997). Aggregation reroutes molecules from a recycling to a vesicle-mediated secretion pathway during reticulocyte maturation. J. Cell Sci. 110 (Pt 16), 1867-1877
115. Villarroya-Beltri, C., Baixauli, F., Gutierrez-Vazquez, C., Sanchez-Madrid, F., and Mittelbrunn, M. (2014). Sorting it out: regulation of exosome loading. Semin. Cancer Biol. 28, 3-13. doi: 10.1016/j.semcancer.2014.04.009
116. Villarroya-Beltri, C., Gutierrez-Vazquez, C., Sanchez-Cabo, F., Perez-Hernandez, D., Vazquez, J., Martin-Cofreces, N., et al. (2013a). Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat. Commun. 4, 2980. doi: 10.1038/ncomms3980
117. Villarroya-Beltri, C., Gutierrez-Vazquez, C., Sanchez-Cabo, F., Perez-Hernandez, D., Vazquez, J., Martin-Cofreces, N., et al. (2013b). Sumoylated hnRNPA2B1 controls the sorting of miRNAs into exosomes through binding to specific motifs. Nat. Commun. 4, 2980. doi: 10.1038/ncomms3980
118. Wang, G., Dinkins, M., He, Q., Zhu, G., Poirier, C., Campbell, A., et al. (2012). Astrocytes secrete exosomes enriched with proapoptotic ceramide and prostate apoptosis response 4 (PAR-4): potential mechanism of apoptosis induction in Alzheimer disease (AD). J. Biol. Chem. 287, 21384-21395. doi: 10.1074/jbc. M112.340513
119. Wang, S., Cesca, F., Loers, G., Schweizer, M., Buck, F., Benfenati, F., et al. (2011). Synapsin I is an oligomannose-carrying glycoprotein, acts as an oligomannose-binding lectin, and promotes neurite outgrowth and neuronal survival when released via glia-derived exosomes. J. Neurosci. 31, 7275-7290. doi: 10.1523/JNEUROSCI.6476-10.2011
120. Wiklander, O. P., Nordin, J. Z., O'loughlin, A., Gustafsson, Y., Corso, G., Mager, I., et al. (2015). Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting. J. Extracell. Vesicl. 4:26316. doi: 10.3402/jev.v4.26316
121. Yamanaka, K., Boillee, S., Roberts, E. A., Garcia, M. L., Mcalonis-Downes, M., Mikse, O. R., et al. (2008). Mutant SOD1 in cell types other than motor neurons and oligodendrocytes accelerates onset of disease in ALS mice. Proc. Natl. Acad. Sci. U.S.A. 105, 7594-7599. doi: 10.1073/pnas.0802556105
122. Yang, Y., Keene, C. D., Peskind, E. R., Galasko, D. R., Hu, S. C., Cudaback, E., et al. (2015). Cerebrospinal Fluid Particles in Alzheimer Disease and Parkinson Disease. J. Neuropathol. Exp. Neurol. 74, 672-687. doi: 10.1097/NEN.0000000000000207
123. Yuyama, K., Sun, H., Sakai, S., Mitsutake, S., Okada, M., Tahara, H., et al. (2014). Decreased amyloid-beta pathologies by intracerebral loading of glycosphingolipid-enriched exosomes in Alzheimer model mice. J. Biol. Chem. 289, 24488-24498. doi: 10.1074/jbc. M114.577213
124. Yuyama, K., Sun, H., Usuki, S., Sakai, S., Hanamatsu, H., Mioka, T., et al. (2015). A potential function for neuronal exosomes: sequestering intracerebral amyloid-beta peptide. FEBS Lett. 589, 84-88. doi: 10.1016/j.febslet.2014.11.027