Extracellular vesicles in brain tumors and neurodegenerative diseases

Frontiers in Molecular Neuroscience

Volumn 10, Issue , 2017, Pages

  Ciregia, Federica ^a   Urbani, Andrea ^b,c   Palmisano, Giuseppe ^c,d  

^a UNIVERSITY OF PISA   (Italy)

^b CATHOLIC UNIVERSITY   (Italy)

^c IRCCS FONDAZIONE SANTA LUCIA   (Italy)

^d UNIVERSITY OF SÃO PAULO   (Brazil)

Author keywords

Biomarkers; Brain tumors; Central nervous system; Exosomes; Neurodegenerative diseases

Indexed keywords

ALZHEIMER DISEASE; AMYOTROPHIC LATERAL SCLEROSIS; BRAIN TUMOR; DEGENERATIVE DISEASE; EXOSOME; GLIOBLASTOMA; HUMAN; HUNTINGTON CHOREA; MASS SPECTROMETRY; MEDULLOBLASTOMA; MULTIPLE SCLEROSIS; NEUROBLASTOMA; PARKINSON DISEASE; PRION DISEASE; REVIEW; SYNAPTIC TRANSMISSION; TUMOR GROWTH;

EID: 85032363985     PISSN: 16625099     EISSN: None     Source Type: Journal    
DOI: 10.3389/fnmol.2017.00276     Document Type: Review

References (181)

1. Abels, E. R., and Breakefield, X. O. (2016). Introduction to extracellular vesicles: biogenesis, RNA cargo selection, content, release, and uptake. Cell. Mol. Neurobiol. 36, 301–312. doi: 10.1007/s10571-016-0366-z
2. Agosta, F., Dalla Libera, D., Spinelli, E. G., Finardi, A., Canu, E., Bergami, A., et al. (2014). Myeloid microvesicles in cerebrospinal fluid are associated with myelin damage and neuronal loss in mild cognitive impairment and Alzheimer disease. Ann. Neurol. 76, 813–825. doi: 10.1002/ana.24235
3. Akers, J. C., Ramakrishnan, V., Kim, R., Phillips, S., Kaimal, V., Mao, Y., et al. (2015). miRNA contents of cerebrospinal fluid extracellular vesicles in glioblastoma patients. J. Neurooncol. 123, 205–216. doi: 10.1007/s11060-015-1784-3
4. Akers, J. C., Ramakrishnan, V., Kim, R., Skog, J., Nakano, I., Pingle, S., et al. (2013). MiR-21 in the extracellular vesicles (EVs) of cerebrospinal fluid (CSF): a platform for glioblastoma biomarker development. PLoS ONE 8:e78115. doi: 10.1371/journal.pone.0078115
5. Alais, S., Simoes, S., Baas, D., Lehmann, S., Raposo, G., Darlix, J. L., et al. (2008). Mouse neuroblastoma cells release prion infectivity associated with exosomal vesicles. Biol. Cell 100, 603–615. doi: 10.1042/BC20080025
6. Alonso, A., Zaidi, T., Novak, M., Grundke-Iqbal, I., and Iqbal, K. (2001). Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments. Proc. Natl. Acad. Sci. U.S.A. 98, 6923–6928. doi: 10.1073/pnas.121119298
7. Alvarez-Erviti, L., Rodriguez-Oroz, M. C., Cooper, J. M., Caballero, C., Ferrer, I., Obeso, J. A., et al. (2010). Chaperone-mediated autophagy markers in Parkinson's disease brains. Arch. Neurol. 67, 1464–1472. doi: 10.1001/archneurol.2010.198
8. Alvarez-Erviti, L., Seow, Y., Yin, H., Betts, C., Lakhal, S., and Wood, M. J. (2011a). Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nat. Biotechnol. 29, 341–345. doi: 10.1038/nbt.1807
9. Alvarez-Erviti, L., Seow, Y., Schapira, A. H., Gardiner, C., Sargent, I. L., Wood, M. J., et al. (2011b). Lysosomal dysfunction increases exosome-mediated alpha-synuclein release and transmission. Neurobiol. Dis. 42, 360–367. doi: 10.1016/j.nbd.2011.01.029
10. An, K., Klyubin, I., Kim, Y., Jung, J. H., Mably, A. J., O'Dowd, S. T., et al. (2013). Exosomes neutralize synaptic-plasticity-disrupting activity of Aβ assemblies in vivo. Mol. Brain 6:47. doi: 10.1186/1756-6606-6-47
11. 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
12. Apolinário, T. A., Paiva, C. L., and Agostinho, L. A. (2017). Intermediate alleles of Huntington's disease HTT gene in different populations worldwide: a systematic review. Genet. Mol. Res. 16, 1–11. doi: 10.4238/gmr16029648
13. 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
14. Ban, L. A., Shackel, N. A., and McLennan, S. V. (2016). Extracellular vesicles: a new frontier in biomarker discovery for non-alcoholic fatty liver disease. Int. J. Mol. Sci. 17:376. doi: 10.3390/ijms17030376
15. 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
16. 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
17. Biju, K., Zhou, Q., Li, G., Imam, S. Z., Roberts, J. L., Morgan, W. W., et al. (2010). Macrophage mediated GDNF delivery protects against dopaminergic neurodegeneration: a therapeutic strategy for Parkinson's disease. Mol. Ther. 18, 1536–1544. doi: 10.1038/mt.2010.107
18. Bisaro, B., Mandili, G., Poli, A., Piolatto, A., Papa, V., Novelli, F., et al. (2015). Proteomic analysis of extracellular vesicles from medullospheres reveals a role for iron in the cancer progression of medulloblastoma. Mol. Cell. Ther. 3:8. doi: 10.1186/s40591-015-0045-3
19. Blennow, K., de Leon, M. J., and Zetterberg, H. (2006). Alzheimer's disease. Lancet 368, 387–403. doi: 10.1016/S0140-6736(06)69113-7
20. Bonafede, R., Scambi, I., Peroni, D., Potrich, V., Boschi, F., Benati, D., et al. (2016). Exosome derived from murine adipose-derived stromal cells: neuroprotective effect on in vitro model of amyotrophic lateral sclerosis. Exp. Cell Res. 340, 150–158. doi: 10.1016/j.yexcr.2015.12.009
21. Bozzoni, V., Pansarasa, O., Diamanti, L., Nosari, G., Cereda, C., and Ceroni, M. (2016). Amyotrophic lateral sclerosis and environmental factors. Funct. Neurol.31, 7–19. doi: 10.11138/FNeur/2016.31.1.007
22. Browne, P., Chandraratna, D., Angood, C., Tremlett, H., Baker, C., Taylor, B. V., et al. (2014). Atlas of Multiple Sclerosis (2013): a growing global problem with widespread inequity. Neurology 83, 1022–1024. doi: 10.1212/WNL.0000000000000768
23. Bulloj, A., Leal, M. C., Xu, H., Castaño, E. M., and Morelli, L. (2010). Insulin-degrading enzyme sorting in exosomes: a secretory pathway for a key brain amyloid-β degrading protease. J. Alzheimers. Dis. 19, 79–95. doi: 10.3233/JAD-2010-1206
24. Burns, A., and Iliffe, S. (2009). Alzheimer's disease. BMJ 338:b158. doi: 10.1136/bmj.b158
25. Cervenakova, L., Saá, P., Yakovleva, O., Vasilyeva, I., de Castro, J., Brown, P., et al. (2016). Are prions transported by plasma exosomes? Transfus. Apher. Sci. 55, 70–83. doi: 10.1016/j.transci.2016.07.013
26. Challagundla, K. B., Wise, P. M., Neviani, P., Chava, H., Murtadha, M., Xu, T., et al. (2015). Exosome-mediated transfer of microRNAs within the tumor microenvironment and neuroblastoma resistance to chemotherapy. J. Natl. Cancer Inst. 107:pii: djv135. doi: 10.1093/jnci/djv135
27. 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
28. Cheung, N. K., and Dyer, M. A. (2013). Neuroblastoma: developmental biology, cancer genomics and immunotherapy. Nat. Rev. Cancer 13, 397–411. doi: 10.1038/nrc3526
29. Chiò, A., Logroscino, G., Traynor, B. J., Collins, J., Simeone, J. C., Goldstein, L. A., et al. (2013). Global epidemiology of amyotrophic lateral sclerosis: a systematic review of the published literature. Neuroepidemiology 41, 118–130. doi: 10.1159/000351153
30. Coluccia, D., Figuereido, C., Isik, S., Smith, C., and Rutka, J. T. (2016). Medulloblastoma: tumor biology and relevance to treatment and prognosis paradigm. Curr. Neurol. Neurosci. Rep. 16:43. doi: 10.1007/s11910-016-0644-7
31. 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. Mov. Disord. 29, 1476–1485. doi: 10.1002/mds.25978
32. Crescitelli, R., Lässer, C., Szabó, T. G., Kittel, A., Eldh, M., Dianzani, I., et al. (2013). Distinct RNA profiles in subpopulations of extracellular vesicles: apoptotic bodies, microvesicles and exosomes. J. Extracell. Vesicles 2:20677. doi: 10.3402/jev.v2i0.20677
33. 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
34. D'Asti, E., Chennakrishnaiah, S., Lee, T. H., and Rak, J. (2016). Extracellular vesicles in brain tumor progression. Cell. Mol. Neurobiol. 36, 383–407. doi: 10.1007/s10571-015-0296-1
35. D'Asti, E., Garnier, D., Lee, T. H., Montermini, L., Meehan, B., and Rak, J. (2012). Oncogenic extracellular vesicles in brain tumor progression. Front. Physiol.3:294. doi: 10.3389/fphys.2012.00294
36. del Aguila, M. A., Longstreth, W. T. Jr., McGuire, V., Koepsell, T. D., and van Belle, G. (2003). Prognosis in amyotrophic lateral sclerosis: a population-based study. Neurology 60, 813–819. doi: 10.1212/01.WNL.0000049472.47709.3B
37. De Strooper, B., and Karran, E. (2016). The cellular phase of Alzheimer's disease. Cell 164, 603–615. doi: 10.1016/j.cell.2015.12.056
38. Dhall, G. (2009). Medulloblastoma. J. Child Neurol. 24, 1418–1430. doi: 10.1177/0883073809341668
39. Didiot, M. C., Hall, L. M., Coles, A. H., Haraszti, R. A., Godinho, B. M., Chase, K., et al. (2016). Exosome-mediated delivery of hydrophobically modified siRNA for huntingtin mRNA silencing. Mol. Ther. 24, 1836–1847. doi: 10.1038/mt.2016.126
40. DiFiglia, M., Sapp, E., Chase, K. O., Davies, S. W., Bates, G. P., Vonsattel, J. P., et al. (1997). Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277, 1990–1993. doi: 10.1126/science.277.5334.1990
41. 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
42. Dinkins, M. B., Dasgupta, S., Wang, G., Zhu, G., He, Q., Kong, J. N., et al. (2015). The 5XFAD mouse model of Alzheimer's disease exhibits an age-dependent increase in anti-ceramide IgG and exogenous administration of ceramide further increases anti-ceramide titers and amyloid plaque burden. J. Alzheimers Dis. 46, 55–61. doi: 10.3233/JAD-150088
43. Di Paolo, G., and Kim, T. W. (2011). Linking lipids to Alzheimer's disease: cholesterol and beyond. Nat. Rev. Neurosci. 12, 284–296. doi: 10.1038/nrn3012
44. Dolecek, T. A., Propp, J. M., Stroup, N. E., and Kruchko, C. (2012). CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005–2009. Neuro Oncol. 14, v1–v49. doi: 10.1093/neuonc/nos218
45. Dugas, J. C., Cuellar, T. L., Scholze, A., Ason, B., Ibrahim, A., Emery, B., et al. (2010). Dicer1 and miR-219 are required for normal oligodendrocyte differentiation and myelination. Neuron 65, 597–611. doi: 10.1016/j.neuron.2010.01.027
46. El-Agnaf, O. M., Salem, S. A., Paleologou, K. E., Cooper, L. J., Fullwood, N. J., Gibson, M. J., et al. (2003). Alpha-synuclein implicated in Parkinson's disease is present in extracellular biological fluids, including human plasma. FASEB J. 17, 1945–1947. doi: 10.1096/fj.03-0098fje
47. 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
48. Epple, L. M., Griffiths, S. G., Dechkovskaia, A. M., Dusto, N. L., White, J., Ouellette, R. J., et al. (2012). Medulloblastoma exosome proteomics yield functional roles for extracellular vesicles. PLoS ONE 7:e42064. doi: 10.1371/journal.pone.0042064
49. Fauré, 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
50. Février, B., Laude, H., Raposo, G., and Vilette, D. (2005). Exosomes: carriers of prions? Med. Sci. (Paris) 21, 132–133. doi: 10.1051/medsci/2005212132
51. 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
52. 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. Alzheimers Dement. 11, 600-7.e1. doi: 10.1016/j.jalz.2014.06.008
53. Fong, M. Y., Zhou, W., Liu, L., Alontaga, A. Y., Chandra, M., Ashby, J., et al. (2015). Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis. Nat. Cell Biol. 17, 183–194. doi: 10.1038/ncb3094
54. Fraser, K. B., Rawlins, A. B., Clark, R. G., Alcalay, R. N., Standaert, D. G., and Liu, N. (2016). Parkinson's disease biomarker program consortium., West AB. Ser(P)-1292 LRRK2 in urinary exosomes is elevated in idiopathic Parkinson's disease. Mov. Disord. 31, 1543–1550. doi: 10.1002/mds.26686
55. 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. B Biol. Sci. 369:20130510. doi: 10.1098/rstb.2013.0510
56. Garnier, D., Jabado, N., and Rak, J. (2013). Extracellular vesicles as prospective carriers of oncogenic protein signatures in adult and paediatric brain tumours. Proteomics 13, 1595–1607. doi: 10.1002/pmic.201200360
57. 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
58. Ghidoni, R., Paterlini, A., Albertini, V., Glionna, M., Monti, E., Schiaffonati, L., et al. (2011). Cystatin C is released in association with exosomes: a new tool of neuronal communication which is unbalanced in Alzheimer's disease. Neurobiol. Aging 32, 1435–1442. doi: 10.1016/j.neurobiolaging.2009.08.013
59. Gibson, P., Tong, Y., Robinson, G., Thompson, M. C., Currle, D. S., Eden, C., et al. (2010). Subtypes of medulloblastoma have distinct developmental origins. Nature 468, 1095–1099. doi: 10.1038/nature09587
60. Gilks, W. P., Abou-Sleiman, P. M., Gandhi, S., Jain, S., Singleton, A., Lees, A. J., et al. (2005). A common LRRK2 mutation in idiopathic Parkinson's disease. Lancet 365, 415–416. doi: 10.1016/S0140-6736(05)17830-1
61. Giovannelli, I., Martelli, F., Repice, A., Massacesi, L., Azzi, A., and Giannecchini, S. (2015). Detection of JCPyV microRNA in blood and urine samples of multiple sclerosis patients under natalizumab therapy. J. Neurovirol. 21, 666–670. doi: 10.1007/s13365-015-0325-3
62. Goetzl, E. J., Boxer, A., Schwartz, J. B., Abner, E. L., Petersen, R. C., Miller, B. L., et al. (2015). Low neural exosomal levels of cellular survival factors in Alzheimer's disease. Ann. Clin. Transl. Neurol. 2, 769–773. doi: 10.1002/acn3.211
63. Goetzl, E. J., Kapogiannis, D., Schwartz, J. B., Lobach, I. V., Goetzl, L., Abner, E. L., et al. (2016a). Decreased synaptic proteins in neuronal exosomes of frontotemporal dementia and Alzheimer's disease. FASEB J. 30, 4141–4148. doi: 10.1096/fj.201600816R
64. Goetzl, E. J., Mustapic, M., Kapogiannis, D., Eitan, E., Lobach, I. V., Goetzl, L., et al. (2016b). Cargo proteins of plasma astrocyte-derived exosomes in Alzheimer's disease. FASEB J. 30, 3853–3859. doi: 10.1096/fj.201600756R
65. 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
66. 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
67. Graner, M. W., Alzate, O., Dechkovskaia, A. M., Keene, J. D., Sampson, J. H., Mitchell, D. A., et al. (2009). Proteomic and immunologic analyses of brain tumor exosomes. FASEB J. 23, 1541–1557. doi: 10.1096/fj.08-122184
68. Graner, M. W., Cumming, R. I., and Bigner, D. D. (2007). The heat shock response and chaperones/heat shock proteins in brain tumors: surface expression, release, and possible immune consequences. J. Neurosci. 27, 11214–11227. doi: 10.1523/JNEUROSCI.3588-07.2007
69. Grey, M., Dunning, C. J., Gaspar, R., Grey, C., Brundin, P., Sparr, E., et al. (2015). Acceleration of α-synuclein aggregation by exosomes. J. Biol. Chem. 290, 2969–2982. doi: 10.1074/jbc.M114.585703
70. Grundke-Iqbal, I., Iqbal, K., Tung, Y. C., Quinlan, M., Wisniewski, H. M., and Binder, L. I. (1986). Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc. Natl. Acad. Sci. U.S.A. 83, 4913–4917. doi: 10.1073/pnas.83.13.4913
71. Gui, Y., Liu, H., Zhang, L., Lv, W., and Hu, X. (2015). Altered microRNA profiles in cerebrospinal fluid exosome in Parkinson disease and Alzheimer disease. Oncotarget 6, 37043–37053. doi: 10.18632/oncotarget.6158
72. Guo, B. B., Bellingham, S. A., and Hill, A. F. (2015). The neutral sphingomyelinase pathway regulates packaging of the prion protein into exosomes. J. Biol. Chem.290, 3455–3467. doi: 10.1074/jbc.M114.605253
73. Guo, B. B., Bellingham, S. A., and Hill, A. F. (2016). Stimulating the release of exosomes increases the intercellular transfer of prions. J. Biol. Chem. 291, 5128–5137. doi: 10.1074/jbc.M115.684258
74. Haag, M. D., Hofman, A., Koudstaal, P. J., Stricker, B. H., and Breteler, M. M. (2009). Statins are associated with a reduced risk of Alzheimer disease regardless of lipophilicity. The Rotterdam Study. J. Neurol. Neurosurg. Psychiatry 80, 13–17. doi: 10.1136/jnnp.2008.150433
75. Haney, M. J., Klyachko, N. L., Zhao, Y., Gupta, R., Plotnikova, E. G., He, Z., et al. (2015). Exosomes as drug delivery vehicles for Parkinson's disease therapy. J. Control. Release 207, 18–30. doi: 10.1016/j.jconrel.2015.03.033
76. Harischandra, D. S., Kondru, N., Martin, D. P., Kanthasamy, A., Jin, H., Anantharam, V., et al. (2014). Role of proteolytic activation of protein kinase Cδ in the pathogenesis of prion disease. Prion 8, 143–153. doi: 10.4161/pri.28369
77. Harshyne, L. A., Hooper, K. M., Andrews, E. G., Nasca, B. J., Kenyon, L. C., Andrews, D. W., et al. (2015). Glioblastoma exosomes and IGF-1R/AS-ODN are immunogenic stimuli in a translational research immunotherapy paradigm. Cancer Immunol. Immunother. 64, 299–309. doi: 10.1007/s00262-014-1622-z
78. Harshyne, L. A., Nasca, B. J., Kenyon, L. C., Andrews, D. W., and Hooper, D. C. (2016). Serum exosomes and cytokines promote a T-helper cell type 2 environment in the peripheral blood of glioblastoma patients. Neuro Oncol. 18, 206–215. doi: 10.1093/neuonc/nov107
79. Haug, B. H., Hald, Ø. H., Utnes, P., Roth, S. A., Løkke, C., Flægstad, T., et al. (2015). Exosome-like extracellular vesicles from MYCN-amplified neuroblastoma cells contain oncogenic miRNAs. Anticancer Res. 35, 2521–2530.
80. Hoshino, A., Costa-Silva, B., Shen, T. L., Rodrigues, G., Hashimoto, A., Tesic Mark, M., et al. (2015). Tumour exosome integrins determine organotropic metastasis. Nature 527, 329–335. doi: 10.1038/nature15756
81. Hung, A. S., Liang, Y., Chow, T. C., Tang, H. C., Wu, S. L., Wai, M. S., et al. (2016). Mutated tau, amyloid and neuroinflammation in Alzheimer disease-A brief review. Prog. Histochem. Cytochem. 51, 1–8. doi: 10.1016/j.proghi.2016.01.001
82. Jacobsson, J., Jonsson, P. A., Andersen, P. M., Forsgren, L., and Marklund, S. L. (2001). Superoxide dismutase in CSF from amyotrophic lateral sclerosis patients with and without CuZn-superoxide dismutase mutations. Brain 124, 1461–1466. doi: 10.1093/brain/124.7.1461
83. Janel, N., Alexopoulos, P., Badel, A., Lamari, F., Camproux, A. C., Lagarde, J., et al. (2017). Combined assessment of DYRK1A, BDNF and homocysteine levels as diagnostic marker for Alzheimer's disease. Transl. Psychiatry 7:e1154. doi: 10.1038/tp.2017.123
84. Johnson, R., Zuccato, C., Belyaev, N. D., Guest, D. J., Cattaneo, E., and Buckley, N. J. (2008). A microRNA-based gene dysregulation pathway in Huntington's disease. Neurobiol. Dis. 29, 438–445. doi: 10.1016/j.nbd.2007.11.001
85. Joshi, P., Turola, E., Ruiz, A., Bergami, A., Libera, D. D., Benussi, L., et al. (2014). Microglia convert aggregated amyloid-β into neurotoxic forms through the shedding of microvesicles. Cell Death Differ. 21, 582–593. doi: 10.1038/cdd.2013.180
86. Kalamvoki, M., and Deschamps, T. (2016). Extracellular vesicles during Herpes Simplex Virus type 1 infection: an inquire. Virol. J. 13:63. doi: 10.1186/s12985-016-0518-2
87. Kalluri, R. (2016). The biology and function of exosomes in cancer. J. Clin. Invest. 126, 1208–1215. doi: 10.1172/JCI81135
88. Kandalepas, P. C., and Vassar, R. (2012). Identification and biology of β-secretase. J. Neurochem. 120, 55–61. doi: 10.1111/j.1471-4159.2011.07512.x
89. Karran, E., Mercken, M., and De Strooper, B. (2011). The amyloid cascade hypothesis for Alzheimer's disease: an appraisal for the development of therapeutics. Nat. Rev. Drug Discov. 10, 698–712. doi: 10.1038/nrd3505
90. Kaur, S. J., McKeown, S. R., and Rashid, S. (2016). Mutant SOD1 mediated pathogenesis of Amyotrophic lateral sclerosis. Gene 577, 109–118. doi: 10.1016/j.gene.2015.11.049
91. Kore, R. A., and Abraham, E. C. (2014). Inflammatory cytokines, interleukin-1 beta and tumor necrosis factor-alpha, upregulated in glioblastoma multiforme, raise the levels of CRYAB in exosomes secreted by U373 glioma cells. Biochem. Biophys. Res. Commun. 453, 326–331. doi: 10.1016/j.bbrc.2014.09.068
92. Kucharzewska, P., Christianson, H. C., Welch, J. E., Svensson, K. J., Fredlund, E., Ringnér, M., et al. (2013). Exosomes reflect the hypoxic tatus of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development. Proc. Natl. Acad. Sci. U.S.A. 110, 7312–7317. doi: 10.1073/pnas.1220998110
93. Kuhlmann, T., Mirion, V., Cui, Q., Wegner, C., Antel, J., and Bruck, W. (2008). Differentiation block of oligodendroglial progenitor cells as a cause for remyelination failure in chronic multiple sclerosis. Brain 131, 1749–1758. doi: 10.1093/brain/awn096
94. Lafon-Cazal, M., Adjali, O., Galéotti, N., Poncet, J., Jouin, P., Homburger, V., et al. (2003). Proteomic analysis of astrocytic secretion in the mouse. Comparison with the cerebrospinal fluid proteome. J. Biol. Chem. 278, 24438–24448. doi: 10.1074/jbc.M211980200
95. Lautenschläger, J., Kaminski, C. F., and Kaminski Schierle, G. S. (2017). α-synuclein-regulator of exocytosis, endocytosis, or both? Trends Cell Biol. 27, 468–479. doi: 10.1016/j.tcb.2017.02.002
96. Lee, M., Ban, J. J., Kim, K. Y., Jeon, G. S., Im, W., Sung, J. J., et al. (2016a). Adipose-derived stem cell exosomes alleviate pathology of amyotrophic lateral sclerosis in vitro. Biochem. Biophys. Res. Commun. 479, 434–439. doi: 10.1016/j.bbrc.2016.09.069
97. Lee, M., Liu, T., Im, W., and Kim, M. (2016b). Exosomes from adipose-derived stem cells ameliorate phenotype of Huntington's disease in vitro model. Eur. J. Neurosci. 44, 2114–2119. doi: 10.1111/ejn.13275
98. Lee, S. T., Im, W., Ban, J. J., Lee, M., Jung, K. H., Lee, S. K., et al. (2017). Exosome-based delivery of miR-124 in a Huntington's disease model. J. Mov. Disord. 10, 45–52. doi: 10.14802/jmd.16054
99. Leshchyns'ka, I., and Sytnyk, V. (2016). Synaptic cell adhesion molecules in Alzheimer's disease. Neural Plast. 2016:6427537. doi: 10.1155/2016/6427537
100. Li, X., Alafuzoff, I., Soininen, H., Winblad, B., and Pei, J. J. (2005). Levels of mTOR and its downstream targets 4E-BP1, eEF2, and eEF2 kinase in relationships with tau in Alzheimer's disease brain. FEBS J. 272, 4211–4220. doi: 10.1111/j.1742-4658.2005.04833.x
101. 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
102. Mallawaaratchy, D. M., Hallal, S., Russell, B., Ly, L., Ebrahimkhani, S., Wei, H., et al. (2017). Comprehensive proteome profiling of glioblastoma-derived extracellular vesicles identifies markers for more aggressive disease. J. Neurooncol. 131, 233–244. doi: 10.1007/s11060-016-2298-3
103. Manterola, L., Guruceaga, E., Gállego Pérez-Larraya, J., González-Huarriz, M., Jauregui, P., Tejada, S., et al. (2014). A small non-coding RNA signature found in exosomes of GBM patient serum as a diagnostic tool. Neuro-oncology 16, 520–527. doi: 10.1093/neuonc/not218
104. Marconi, S., Bonaconsa, M., Scambi, I., Squintani, G. M., Rui, W., Turano, E., et al. (2013). Systemic treatment with adipose-derived mesenchymal stem cells ameliorates clinical and pathological features in the amyotrophic lateral sclerosis murine model. Neuroscience 248, 333–343. doi: 10.1016/j.neuroscience.2013.05.034
105. 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
106. Medina, M., Hernández, F., and Avila, J. (2016). New features about tau function and dysfunction. Biomolecules 6:E21. doi: 10.3390/biom6020021
107. Minagar, A., Jy, W., Jimenez, J. J., Sheremata, W. A., Mauro, L. M., Mao, W. W., et al. (2001). Elevated plasma endothelial microparticles in multiple sclerosis. Neurology 56, 1319–1324. doi: 10.1212/WNL.56.10.1319
108. Mondola, P., Annella, T., Santillo, M., and Santangelo, F. (1996). Evidence for secretion of cytosolic CuZn superoxide dismutase by Hep G2 cells and human fibroblasts. Int. J. Biochem. Cell Biol. 28, 677–681. doi: 10.1016/1357-2725(96)00004-0
109. Mourad, P. D., Farrell, L., Stamps, L. D., Chicoine, M. R., and Silbergeld, D. L. (2005). Why are systemic glioblastoma metastases rare? Systemic and cerebral growth of mouse glioblastoma. Surg. Neurol. 63, 511–519; discussion 519. doi: 10.1016/j.surneu.2004.08.062
110. Muller, L., Muller-Haegele, S., Mitsuhashi, M., Gooding, W., Okada, H., and Whiteside, T. L. (2015). Exosomes isolated from plasma of glioma patients enrolled in a vaccination trial reflect antitumor immune activity and might predict survival. Oncoimmunology 4:e1008347. doi: 10.1080/2162402X.2015.1008347
111. Münch, C., O'Brien, J., and Bertolotti, A. (2011). Prion-like propagation of mutant superoxide dismutase-1 misfolding in neuronal cells. Proc. Natl. Acad. Sci. U.S.A. 108, 3548–3553. doi: 10.1073/pnas.1017275108
112. Musunuri, S., Khoonsari, P. E., Mikus, M., Wetterhall, M., Häggmark-Mänberg, A., Lannfelt, L., et al. (2016). Increased levels of extracellular microvesicle markers and decreased levels of endocytic/exocytic proteins in the Alzheimer's disease brain. J. Alzheimers. Dis. 54, 1671–1686. doi: 10.3233/JAD-160271
113. Ning, B. F., Ding, J., Yin, C., Zhong, W., Wu, K., Zeng, X., et al. (2010). Hepatocyte nuclear factor 4α suppresses the development of hepatocellular carcinoma. Cancer Res. 70, 7640–7651. doi: 10.1158/0008-5472.CAN-10-0824
114. Ohali, A., Avigad, S., Ash, S., Goshen, Y., Luria, D., Feinmesser, M., et al. (2006). Telomere length is a prognostic factor in neuroblastoma. Cancer 107, 1391–1399. doi: 10.1002/cncr.22132
115. Palmieri, D., Smith, Q. R., Lockman, P. R., Bronder, J., Gril, B., Chambers, A. F., et al. (2006). Brain metastases of breast cancer. Breast Dis. 26, 139–147. doi: 10.3233/BD-2007-26112
116. Pan, B. T., and Johnstone, R. M. (1983). Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor. Cell 33, 967–978. doi: 10.1016/0092-8674(83)90040-5
117. Park, J. R., Eggert, A., and Caron, H. (2010). Neuroblastoma: biology, prognosis, and treatment. Hematol. Oncol. Clin. North Am. 24, 65–86. doi: 10.1016/j.hoc.2009.11.011
118. Park, S., Ahn, E. S., and Kim, Y. (2015). Neuroblastoma SH-SY5Y cell-derived exosomes stimulate dendrite-like outgrowths and modify the differentiation of A375 melanoma cells. Cell Biol. Int. 39, 379–387. doi: 10.1002/cbin.10401
119. Peinado, H., Alecković, M., Lavotshkin, S., Matei, I., Costa-Silva, B., Moreno-Bueno, G., et al. (2012). Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nat. Med. 18, 883–891. doi: 10.1038/nm.2753
120. Perez-Gonzalez, R., Gauthier, S. A., Kumar, A., and Levy, E. (2012). The exosome secretory pathway transports amyloid precursor protein carboxyl-terminal fragments from the cell into the brain extracellular space. J. Biol. Chem. 287, 43108–43115. doi: 10.1074/jbc.M112.404467
121. Polanco, J. C., Scicluna, B. J., Hill, A. F., and Götz, J. (2016). Extracellular vesicles isolated from brains of rTg4510 mice seed tau aggregation in a threshold-dependent manner. J. Biol. Chem. 291, 12445–12466. doi: 10.1074/jbc.M115.709485
122. Prusiner, S. B. (1996). Molecular biology and pathogenesis of prion diseases. Trends Biochem. Sci. 21, 482–487. doi: 10.1016/S0968-0004(96)10063-3
123. Pusic, A. D., Pusic, K. M., and Kraig, R. P. (2014a). What are exosomes and how can they be used in multiple sclerosis therapy? Expert Rev. Neurother. 14, 353–355. doi: 10.1586/14737175.2014.890893
124. Pusic, A. D., Pusic, K. M., Clayton, B. L., and Kraig, R. P. (2014b). IFNγ-stimulated dendritic cell exosomes as a potential therapeutic for remyelination. J. Neuroimmunol. 266, 12–23. doi: 10.1016/j.jneuroim.2013.10.014
125. Pusic, A. D., and Kraig, R. P. (2014). Youth and environmental enrichment generate serum exosomes containing miR-219 that promote CNS myelination. Glia 62, 284–299. doi: 10.1002/glia.22606
126. Pusic, K. M., Pusic, A. D., and Kraig, R. P. (2016). Environmental enrichment stimulates immune cell secretion of exosomes that promote CNS myelination and may regulate inflammation. Cell. Mol. Neurobiol. 36, 313–325. doi: 10.1007/s10571-015-0269-4
127. Querfurth, H. W., and LaFerla, F. M. (2010). Alzheimer's disease. N. Engl. J. Med. 362, 329–344. doi: 10.1056/NEJMra0909142
128. 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
129. Raposo, G., and Stoorvogel, W. (2013). Extracellular vesicles: exosomes, microvesicles, and friends. J. Cell Biol. 200, 373–383. doi: 10.1083/jcb.201211138
130. Rowland, L. P. (1994). Amyotrophic lateral sclerosis. Curr. Opin. Neurol. 7, 310–315. doi: 10.1097/00019052-199408000-00006
131. Saá, P., Yakovleva, O., de Castro, J., Vasilyeva, I., De Paoli, S. H., Simak, J., et al. (2014). First demonstration of transmissible spongiform encephalopathy-associated prion protein (PrPTSE) in extracellular vesicles from plasma of mice infected with mouse-adapted variant Creutzfeldt-Jakob disease by in vitroamplification. J. Biol. Chem. 289, 29247–29260. doi: 10.1074/jbc.M114.589564
132. Saba, R., Goodman, C. D., Huzarewich, R. L., Robertson, C., and Booth, S. A. (2008). A miRNA signature of prion induced neurodegeneration. PLoS ONE 3:e3652. doi: 10.1371/journal.pone.0003652
133. Sáenz-Cuesta, M., Irizar, H., Castillo-Triviño, T., Muñoz-Culla, M., OsorioQuerejeta, I., Prada, A., et al. (2014). Circulating microparticles reflect treatment effects and clinical status in multiple sclerosis. Biomark. Med. 8, 653–661. doi: 10.2217/bmm.14.9
134. Saman, S., Kim, W., Raya, M., Visnick, Y., Miro, S., Saman, S., 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
135. Saman, S., Lee, N. C., Inoyo, I., Jin, J., Li, Z., Doyle, T., et al. (2014). Proteins recruited to exosomes by tau overexpression implicate novel cellular mechanisms linking tau secretion with Alzheimer's disease. J. Alzheimers. Dis. 40, S47–S70. doi: 10.3233/JAD-132135
136. Scheltens, P., Blennow, K., Breteler, M. M., de Strooper, B., Frisoni, G. B., Salloway, S., et al. (2016). Alzheimer's disease. Lancet 388, 505–517. doi: 10.1016/S0140-6736(15)01124-1
137. Scolding, N. J., Morgan, B. P., Houston, W. A., Linington, C., Campbell, A. K., and Compston, D. A. (1989). Vesicular removal by oligodendrocytes of membrane attack complexes formed by activated complement. Nature 339, 620–622. doi: 10.1038/339620a0
138. Selkoe, D. J., and Schenk, D. (2003). Alzheimer's disease: molecular understanding predicts amyloid-based therapeutics. Annu. Rev. Pharmacol. Toxicol. 43, 545–584. doi: 10.1146/annurev.pharmtox.43.100901.140248
139. Setti, M., Osti, D., Richichi, C., Ortensi, B., Del Bene, M., Fornasari, L., et al. (2015). Extracellular vesicle-mediated transfer of CLIC1 protein is a novel mechanism for the regulation of glioblastoma growth. Oncotarget 6, 31413–31427. doi: 10.18632/oncotarget.5105
140. Shao, H., Chung, J., Balaj, L., Charest, A., Bigner, D. D., Carter, B. S., et al. (2012). Protein typing of circulating microvesicles allows real-time monitoring of glioblastoma therapy. Nat. Med. 18, 1835–1840. doi: 10.1038/nm.2994
141. Shao, H., Chung, J., Lee, K., Balaj, L., Min, C., Carter, B. S., et al. (2015). Chip-based analysis of exosomal mRNA mediating drug resistance in glioblastoma. Nat. Commun. 6:6999. doi: 10.1038/ncomms7999
142. Sharples, R. A., Vella, L. J., Nisbet, R. M., Naylor, R., Perez, K., Barnham, K. J., et al. (2008). Inhibition of gamma-secretase causes increased secretion of amyloid precursor protein C-terminal fragments in association with exosomes. FASEB J. 22, 1469–1478. doi: 10.1096/fj.07-9357com
143. Sheremata, W. A., Jy, W., Delgado, S., Minagar, A., McLarty, J., and Ahn, Y. (2006). Interferon-β1a reduces plasma CD31+ endothelial microparticles (CD31+EMP) in multiple sclerosis. J. Neuroinflammation 3:23. doi: 10.1186/1742-2094-3-23
144. Sheremata, W. A., Jy, W., Horstman, L. L., Ahn, Y. S., Alexander, J. S., and Minagar, A. (2008). Evidence of platelet activation in multiple sclerosis. J. Neuroinflammation 5:27. doi: 10.1186/1742-2094-5-27
145. Shi, M., Kovac, A., Korff, A., Cook, T. J., Ginghina, C., Bullock, K. M., et al. (2016). CNS tau efflux via exosomes is likely increased in Parkinson's disease but not in Alzheimer's disease. Alzheimers Dement. 12, 1125–1131. doi: 10.1016/j.jalz.2016.04.003
146. Shi, M., Liu, C., Cook, T. J., Bullock, K. M., Zhao, Y., Ginghina, C., et al. (2014). Plasma exosomal α-synuclein is likely CNS-derived and increased in Parkinson's disease. Acta Neuropathol. 128, 639–650. doi: 10.1007/s00401-014-1314-y
147. Skog, J., Würdinger, T., van Rijn, S., Meijer, D. H., Gainche, L., Sena-Esteves, M., et al. (2008). Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers. Nat. Cell Biol. 10, 1470–1476. doi: 10.1038/ncb1800
148. Smalheiser, N. R. (2007). Exosomal transfer of proteins and RNAs at synapses in the nervous system. Biol. Direct 2:35. doi: 10.1186/1745-6150-2-35
149. Smith, V., Dai, F., Spitz, M., Peters, G. J., Fiebig, H. H., Hussain, A., et al. (2009). Telomerase activity and telomere length in human tumor cells with acquired resistance to anticancer agents. J. Chemother. 21, 542–549. doi: 10.1179/joc.2009.21.5.542
150. Steegmann-Olmedillas, J. L. (2011). The role of iron in tumour cell proliferation. Clin. Transl. Oncol. 13, 71–76. doi: 10.1007/s12094-011-0621-1
151. Stuendl, A., Kunadt, M., Kruse, N., Bartels, C., Moebius, W., Danzer, K. M., et al. (2016). Induction of α-synuclein aggregate formation by CSF exosomes from patients with Parkinson's disease and dementia with Lewy bodies. Brain 139, 481–494. doi: 10.1093/brain/awv346
152. Sundelöf, J., Arnlöv, J., Ingelsson, E., Sundström, J., Basu, S., Zethelius, B., et al. (2008). Serum cystatin C and the risk of Alzheimer's disease in elderly men. Neurology 71, 1072–1079. doi: 10.1212/01.wnl.0000326894.40353.93
153. Tamboli, I. Y., Barth, E., Christian, L., Siepmann, M., Kumar, S., Singh, S., et al. (2010). Statins promote the degradation of extracellular amyloid beta-peptide by microglia via stimulation of exosome-associated insulin-degrading enzyme (IDE) secretion. J. Biol. Chem. 285, 37405–37414. doi: 10.1074/jbc.M110.149468
154. Tang, Z., Ioja, E., Bereczki, E., Hultenby, K., Li, C., Guan, Z., et al. (2015). mTor mediates tau localization and secretion: Implication for Alzheimer's disease. Biochim. Biophys. Acta 1853, 1646–1657. doi: 10.1016/j.bbamcr.2015.03.003
155. Tominaga, N., Kosaka, N., Ono, M., Katsuda, T., Yoshioka, Y., Tamura, K., et al. (2015). Brain metastatic cancer cells release microRNA-181c-containing extracellular vesicles capable of destructing blood-brain barrier. Nat. Commun. 6:6716. doi: 10.1038/ncomms7716
156. Trams, E. G., Lauter, C. J., Salem, N. Jr., and Heine, U. (1981). Exfoliation of membrane ecto-enzymes in the form of micro-vesicles. Biochim. Biophys. Acta. 645, 63–70. doi: 10.1016/0005-2736(81)90512-5
157. Turner, B. J., Atkin, J. D., Farg, M. A., Zang, D. W., Rembach, A., Lopes, E. C., et al. (2005). Impaired extracellular secretion of mutant superoxide dismutase 1 associates with neurotoxicity in familial amyotrophic lateral sclerosis. J. Neurosci. 25, 108–117. doi: 10.1523/JNEUROSCI.4253-04.2005
158. Urushitani, M., Sik, A., Sakurai, T., Nukina, N., Takahashi, R., and Julien, J. P. (2006). Chromogranin-mediated secretion of mutant superoxide dismutase proteins linked to amyotrophic lateral sclerosis. Nat. Neurosci. 9, 108–118. doi: 10.1038/nn1603
159. Vaidya, S., Velázquez-Delgado, E. M., Abbruzzese, G., and Hardy, J. A. (2011). Substrate-induced conformational changes occur in all cleaved forms of caspase-6. J. Mol. Biol. 406, 75–91. doi: 10.1016/j.jmb.2010.11.031
160. Vella, L. J., Hill, A. F., and Cheng, L. (2016). Focus on extracellular vesicles: exosomes and their role in protein trafficking and biomarker potential in Alzheimer's and Parkinson's disease. Int. J. Mol. Sci. 17:173. doi: 10.3390/ijms17020173
161. 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
162. 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
163. Vingtdeux, V., Hamdane, M., Loyens, A., Gelé, P., Drobeck, H., Bégard, S., et al. (2007). Alkalizing drugs induce accumulation of amyloid precursor protein by-products in luminal vesicles of multivesicular bodies. J. Biol. Chem. 282, 18197–18205. doi: 10.1074/jbc.M609475200
164. Vlassov, A. V., Magdaleno, S., Setterquist, R., and Conrad, R. (2012). Exosomes: current knowledge of their composition, biological functions, and diagnostic and therapeutic potentials. Biochim. Biophys. Acta 1820, 940–948. doi: 10.1016/j.bbagen.2012.03.017
165. Volik, S., Alcaide, M., Morin, R. D., and Collins, C. (2016). Cell-free DNA (cfDNA): clinical significance and utility in cancer shaped by emerging technologies. Mol. Cancer Res. 14, 898–908. doi: 10.1158/1541-7786.MCR-16-0044
166. 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
167. Wang, Y., Springer, S., Zhang, M., McMahon, K. W., Kinde, I., Dobbyn, L., et al. (2015). Detection of tumor-derived DNA in cerebrospinal fluid of patients with primary tumors of the brain and spinal cord. Proc. Natl. Acad. Sci. U.S.A. 112, 9704–9709. doi: 10.1073/pnas.1511694112
168. Wu, A., Wei, J., Kong, L. Y., Wang, Y., Priebe, W., Qiao, W., et al. (2010). Glioma cancer stem cells induce immunosuppressive macrophages/microglia. Neuro-oncology 12, 1113–1125. doi: 10.1093/neuonc/noq082
169. Wu, X., Somlo, G., Yu, Y., Palomares, M. R., Li, A. X., Zhou, W., et al. (2012). De novo sequencing of circulating miRNAs identifies novel markers predicting clinical outcome of locally advanced breast cancer. J. Transl. Med. 10:42. doi: 10.1186/1479-5876-10-42
170. Wyant, K. J., Ridder, A. J., and Dayalu, P. (2017). Huntington's disease-update on treatments. Curr. Neurol. Neurosci. Rep. 17:33. doi: 10.1007/s11910-017-0739-9
171. Xue-Shan, Z., Juan, P., Qi, W., Zhong, R., Li-Hong, P., Zhi-Han, T., et al. (2016). Imbalanced cholesterol metabolism in Alzheimer's disease. Clin. Chim. Acta 456, 107–114. doi: 10.1016/j.cca.2016.02.024
172. Yanagisawa, K., Odaka, A., Suzuki, N., and Ihara, Y. (1995). GM1 ganglioside-bound amyloid β-protein (Aβ): a possible form of preamyloid in Alzheimer's disease. Nat. Med. 1, 1062–1066. doi: 10.1038/nm1095-1062
173. Yáñez-Mó, M., Siljander, P. R., Andreu, Z., Zavec, A. B., Borràs, F. E., Buzas, E. I., et al. (2015). Biological properties of extracellular vesicles and their physiological functions. J. Extracell. Vesicles 4:27066. doi: 10.3402/jev.v4.27066
174. Yuyama, K., Sun, H., Mitsutake, S., and Igarashi, Y. (2012). Sphingolipid-modulated exosome secretion promotes clearance of amyloid-β by microglia. J. Biol. Chem. 287, 10977–10989. doi: 10.1074/jbc.M111.324616
175. Yuyama, K., Sun, H., Sakai, S., Mitsutake, S., Okada, M., Tahara, H., et al. (2014). Decreased amyloid-β pathologies by intracerebral loading of glycosphingolipid-enriched exosomes in Alzheimer model mice. J. Biol. Chem. 289, 24488–24498. doi: 10.1074/jbc.M114.577213
176. Yuyama, K., Sun, H., Usuki, S., Sakai, S., Hanamatsu, H., Mioka, T., et al. (2015). A potential function for neuronal exosomes: sequestering intracerebral amyloid-β peptide. FEBS Lett. 589, 84–88. doi: 10.1016/j.febslet.2014.11.027
177. Yuyama, K., Yamamoto, N., and Yanagisawa, K. (2008). Accelerated release of exosome-associated GM1 ganglioside (GM1) by endocytic pathway abnormality: another putative pathway for GM1-induced amyloid fibril formation. J. Neurochem. 105, 217–224. doi: 10.1111/j.1471-4159.2007.05128.x
178. Zhang, L., Zhang, S., Yao, J., Lowery, F. J., Zhang, Q., Huang, W. C., et al. (2015). Microenvironment-induced PTEN loss by exosomal microRNA primes brain metastasis outgrowth. Nature 527, 100–104. doi: 10.1038/nature15376
179. Zhang, X., Abels, E. R., Redzic, J. S., Margulis, J., Finkbeiner, S., and Breakefield, X. O. (2016). Potential transfer of polyglutamine and CAG-repeat RNA in extracellular vesicles in Huntington's disease: background and evaluation in cell culture. Cell. Mol. Neurobiol. 36, 459–470. doi: 10.1007/s10571-016-0350-7
180. Zhao, X., He, X., Han, X., Yu, Y., Ye, F., Chen, Y., et al. (2010). MicroRNA-mediated control of oligodendrocyte differentiation. Neuron 65, 612–626. doi: 10.1016/j.neuron.2010.02.018
181. Zhao, Y., Haney, M. J., Gupta, R., Bohnsack, J. P., He, Z., Kabanov, A. V., et al. (2014). GDNF-transfected macrophages produce potent neuroprotective effects in Parkinson's disease mouse model. PLoS ONE 9:e106867. doi: 10.1371/journal.pone.0106867