Neuroinflammation and depression: Microglia activation, extracellular microvesicles and microRNA dysregulation

Frontiers in Cellular Neuroscience

Volumn 9, Issue DEC, 2015, Pages 1-20

  Brites, Dora ^a,b   Fernandes, Adelaide ^a,b  

^a RESEARCH INSTITUTE FOR MEDICINES IMED ULISBOA   (Portugal)

^b UNIVERSITY OF LISBON   (Portugal)

Author keywords

Astrocytes; Ectosomes; Exosomes; Glia interplay; Microglia; MicroRNAs; Neurodegeneration; Oligodendrocytes

Indexed keywords

COPPER ZINC SUPEROXIDE DISMUTASE; GLIAL FIBRILLARY ACIDIC PROTEIN; HIGH MOBILITY GROUP B PROTEIN; MICRORNA; MICRORNA 124; MICRORNA 124A; MICRORNA 125B; MICRORNA 128; MICRORNA 132; MICRORNA 134; MICRORNA 137; MICRORNA 185; MICRORNA 221; MICRORNA 222; MICRORNA 23; MICRORNA 26; MICRORNA 29; MICRORNA 491 3P; RNA INDUCED SILENCING COMPLEX; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG; VENLAFAXINE;

AMYOTROPHIC LATERAL SCLEROSIS; ASTROCYTE; DEPRESSION; DOWN REGULATION; EXOSOME; GENETIC VARIABILITY; HUMAN; MEMBRANE MICROPARTICLE; MICROGLIA; NERVE DEGENERATION; NERVOUS SYSTEM INFLAMMATION; NEUROBIOLOGY; NEUROMODULATION; NONHUMAN; OLIGODENDROGLIA; PARKINSON DISEASE; PROTEIN EXPRESSION; REVIEW;

EID: 84954068135     PISSN: 16625102     EISSN: None     Source Type: Journal    
DOI: 10.3389/fncel.2015.00476     Document Type: Review

References (258)

1. Absalon, S., Kochanek, D. M., Raghavan, V., and Krichevsky, A. M. (2013). MiR-26b, upregulated in Alzheimer’s disease, activates cell cycle entry, tau-phosphorylation and apoptosis in postmitotic neurons. J. Neurosci. 33, 14645-14659. doi: 10.1523/JNEUROSCI.1327-13.2013
2. Albert, P. R., Benkelfat, C., and Descarries, L. (2012). The neurobiology of depression—revisiting the serotonin hypothesis. I. Cellular and molecular mechanisms. Philos. Trans. R. Soc. Lond. B Biol. Sci. 367, 2378-2381. doi: 10.1098/rstb.2012.0190
3. Alexander, M., Hu, R., Runtsch, M. C., Kagele, D. A., Mosbruger, T. L., Tolmachova, T., et al. (2015). Exosome-delivered microRNAs modulate the inflammatory response to endotoxin. Nat. Commun. 6:7321. doi: 10.1038/ncomms8321
4. Altshuler, L. L., Abulseoud, O. A., Foland-Ross, L., Bartzokis, G., Chang, S., Mintz, J., et al. (2010). Amygdala astrocyte reduction in subjects with major depressive disorder butnot bipolar disorder. BipolarDis. 12, 541-549. doi: 10.1111/j.1399-5618.2010.00838.x
5. 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
6. 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
7. Aston, C., Jiang, L., and Sokolov, B. P. (2005). Transcriptional profiling reveals evidence for signaling and oligodendroglial abnormalities in the temporal cortex from patients with major depressive disorder. Mol. Psychiatry 10, 309-322. doi: 10.1038/sj.mp.4001565
8. Bahrini, I., Song, J. H., Diez, D., and Hanayama, R. (2015). Neuronal exosomes facilitate synaptic pruning by up-regulating complement factors in microglia. Sci. Rep. 5:7989. doi: 10.1038/srep07989
9. Baixauli, F., Lopez-Otin, C., and Mittelbrunn, M. (2014). Exosomes and autophagy: coordinated mechanisms for the maintenance of cellular fitness. Front. Immunol. 5:403. doi: 10.3389/fimmu.2014.00403
10. Bakhti, M., Winter, C., and Simons, M. (2011). Inhibition of myelin membrane sheath formation by oligodendrocyte-derived exosome-like vesicles. J. Biol. Chem. 286, 787-796. doi: 10.1074/jbc.m110.190009
11. Banigan, M. G., Kao, P. F., Kozubek, J. A., Winslow, A. R., Medina, J., Costa, J., et al. (2013). Differential expression of exosomal microRNAs in prefrontal cortices of schizophrenia and bipolar disorder patients. PLoS One 8:e48814. doi: 10.1371/journal.pone.0048814
12. Bargaje, R., Gupta, S., Sarkeshik, A., Park, R., Xu, T., Sarkar, M., et al. (2012). Identification of novel targets for miR-29a using miRNA proteomics. PLoS One 7:e43243. doi: 10.1371/journal.pone.0043243
13. Basso, M., Pozzi, S., Tortarolo, M., Fiordaliso, F., Bisighini, C., Pasetto, L., et al. 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
14. Bauer, J., Hohagen, F., Gimmel, E., Bruns, F., Lis, S., Krieger, S., et al. (1995). Induction of cytokine synthesis and fever suppresses REM sleep and improves mood in patients with major depression. Biol. Psychiatry 38, 611-621. doi: 10.1016/0006-3223(95)00374-x
15. Bellingham, S. A., Coleman, B. M., and Hill, A. F. (2012a). 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
16. Bellingham, S. A., Guo, B. B., Coleman, B. M., and Hill, A. F. (2012b). Exosomes: vehicles for the transfer of toxic proteins associated with neurodegenerative diseases? Front. Physiol. 3:124. doi: 10.3389/fphys.2012.00124
17. Belzeaux, R., Bergon, A., Jeanjean, V., Loriod, B., Formisano-Treziny, C., Verrier, L., et al. (2012). Responder and nonresponder patients exhibit different peripheral transcriptional signatures during major depressive episode Transl. Psychiatry 2:e185. doi: 10.1038/tp.2012.112
18. Benton, T., Staab, J., and Evans, D. L. (2007). Medical co-morbidity in depressive disorders. Ann. Clin. Psychiatry 19, 289-303. doi: 10.1080/10401230701653542
19. Bernimoulin, M., Waters, E. K., Foy, M., Steele, B. M., Sullivan, M., Falet, H., et al. (2009). Differential stimulation of monocytic cells results in distinct populations of microparticles. J. Thromb. Haemost. 7, 1019-1028. doi: 10.1111/j.1538-7836.2009.03434.x
20. Bessa, J. M., Ferreira, D., Melo, I., Marques, F., Cerqueira, J. J., Palha, J. A., et al. The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling. Mol. Psychiatry 14, 764-773, 739. doi: 10.1038/mp.2008.119
21. Bhatnagar, S., Shinagawa, K., Castellino, F. J., and Schorey, J. S. (2007). Exosomes released from macrophages infected with intracellular pathogens stimulate a proinflammatory response in vitro and in vivo. Blood 110, 3234-3244. doi: 10.1182/blood-2007-03-079152
22. Bianco, F., Perrotta, C., Novellino, L., Francolini, M., Riganti, L., Menna, E., et al. Acid sphingomyelinase activity triggers microparticle release from glial cells. EMBO J. 28, 1043-1054. doi: 10.1038/emboj.2009.45
23. 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
24. Biggar, K. K., and Storey, K. B. (2011). The emerging roles of microRNAs in the molecular responses of metabolic rate depression. J. Mol. Cell Biol. 3, 167-175. doi: 10.1093/jmcb/mjq045
25. Brites, D. (2015). Cell ageing: a flourishing field for neurodegenerative diseases. AIMSMol. Sci. 2,225-258. doi: 10.3934/molsci.2015.3.225
26. Brites, D., Gomes, C., Pinheiro, R., and Falcao, A. S. (2015). ‘‘New Insights in the pro- and anti-neurogenic interventions of microglia and their association to gliomas,’’in Microglia:Physiology,Regulation andHealth Implications, ed. E. R. Giffard (NewYork: Nova Biomedical), 67-111.
27. Brites, D., and Vaz, A. R. (2014). Microglia centered pathogenesis in ALS: insights in cell interconnectivity. Front. Cell. Neurosci. 8:117. doi: 10.3389/fncel.2014.00117
28. Bronisz, A., Wang, Y., Nowicki, M. O., Peruzzi, P., Ansari, K. I., Ogawa, D., et al. Extracellular vesicles modulate the glioblastoma microenvironment via a tumor suppression signaling network directed by miR-1. Cancer Res. 74, 738-750. doi: 10.1158/0008-5472.CAN-13-2650
29. Bryniarski, K., Ptak, W., Jayakumar, A., Pullmann, K., Caplan, M. J., Chairoungdua, A., et al. (2013). Antigen-specific, antibody-coated, exosome- like nanovesicles deliver suppressor T-cell microRNA-150 to effector T cells to inhibit contact sensitivity. J. Allergy Clin. Immunol. 132, 170-181. doi: 10.1016/j.jaci.2013.04.048
30. Buzas, E. I., Gyorgy, B., Nagy, G., Falus, A., and Gay, S. (2014). Emerging role of extracellular vesicles in inflammatory diseases. Nat. Rev. Rheumatol. 10, 364. doi: 10.1038/nrrheum.2014.19
31. Cardoso, A. L., Guedes, J. R., and De Lima, M. C. (2015). Role ofmicroRNAs in the regulation of innate immune cells under neuroinflammatory conditions. Curr. Opin. Pharmacol. 26, 1-9. doi: 10.1016/j.coph.2015.09.001
32. Carvalho, A. F., Kohler, C. A., Mcintyre, R. S., Knochel, C., Brunoni, A. R., Thase, M. E., et al. (2015). Peripheral vascular endothelial growth factor as a novel depression biomarker: a meta-analysis. Psychoneuroendocrinology 62, 18-26. doi: 10.1016/j.psyneuen.2015.07.002
33. Castrén, E., and Rantamäki, T. (2010). The role of BDNF and its receptors in depression and antidepressant drug action: reactivation of developmental plasticity. Dev. Neurobiol. 70, 289-297. doi: 10.1002/dneu.20758
34. Chakrabarty, P., Tianbai, L., Herring, A., Ceballos-Diaz, C., Das, P., and Golde, T. E. (2012). Hippocampal expression of murine IL-4 results in exacerbation of amyloid deposition. Mol. Neurodegener. 7:36. doi: 10.1186/1750-1326-7-36
35. Chana, G., Bousman, C. A., Money, T. T., Gibbons, A., Gillett, P., Dean, B., et al. (2013). Biomarker investigations related to pathophysiological pathways in schizophrenia and psychosis. Front. Cell. Neurosci. 7:95. doi: 10.3389/fncel.2013.00095
36. 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
37. Cheng, L. C., Pastrana, E., Tavazoie, M., and Doetsch, F. (2009). miR-124 regulates adult neurogenesis in the subventricular zone stem cell niche. Nat. Neurosci. 12, 399-408. doi: 10.1038/nn.2294
38. Cheng, L., Sharples, R. A., Scicluna, B. J., and Hill, A. F. (2014). Exosomes provide a protective and enriched source of miRNA for biomarker profiling compared to intracellular and cell-free blood. J. Extracell. Vesicles 3:23743 doi: 10.3402/jev.v3.23743
39. Cherry, J. D., Olschowka, J. A., and O’Banion, M. K. (2014). Neuroinflammation and M2 microglia: the good, the bad and the inflamed. J. Neuroinflammation 11:98. doi: 10.1186/1742-2094-11-98
40. Chhor, V., Le Charpentier, T., Lebon, S., Ore, M. V., Celador, I. L., Josserand, J., et al. (2013). Characterization of phenotype markers and neuronotoxic potential of polarised primary microglia in vitro. Brain Behav. Immun. 32, 70-85. doi: 10.1016/j.bbi.2013.02.005
41. Chivet, M., Javalet, C., Laulagnier, K., Blot, B., Hemming, F. J., and Sadoul, R. Exosomes secreted by cortical neurons upon glutamatergic synapse activation specifically interact with neurons. J. Extracell. Vesicles 3:24722. doi: 10.3402/jev.v3.24722
42. Choi, S. H., Aid, S., and Bosetti, F. (2009). The distinct roles of cyclooxygenase-1 and -2 in neuroinflammation: implications for translational research. Trends Pharmacol. Sci. 30, 174-181. doi: 10.1016/j.tips.2009.01.002
43. Choi, H. B., Ryu, J. K., Kim, S. U., and McLarnon, J. G. (2007). Modulation of the purinergic P2X7 receptor attenuates lipopolysaccharide-mediated microglial activation and neuronal damage in inflamed brain. J. Neurosci. 27, 4957-4968. doi: 10.1523/jneurosci.5417-06.2007
44. Cocucci, E., and Meldolesi, J. (2011). Ectosomes. Curr. Biol. 21, R940-R941. doi: 10.1016/j.cub.2011.10.011
45. 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
46. Colton, C. A. (2009). Heterogeneity of microglial activation in the innate immune response in the brain. J. Neuroimmune. Pharmacol. 4, 399-418. doi: 10.1007/s11481-009-9164-4
47. Covington, H. E. III, Lobo, M. K., Maze, I., Vialou, V., Hyman, J. M., Zaman, S., et al. (2010). Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex. J. Neurosci. 30, 16082-16090. doi: 10.1523/JNEUROSCI.1731-10.2010
48. Croce, N., Gelfo, F., Ciotti, M. T., Federici, G., Caltagirone, C., Bernardini, S., et al. NPY modulates miR-30a-5p and BDNF in opposite direction in an in vitro model of Alzheimer disease: a possible role in neuroprotection? Mol. CellBiochem. 376, 189-195. doi: 10.1007/s11010-013-1567-0
49. Czeh, M., Gressens, P., and Kaindl, A. M. (2011). The yin and yang of microglia. Dev. Neurosci. 33, 199-209. doi: 10.1159/000328989
50. Dahl, J., Ormstad, H., Aass, H. C., Malt, U. F., Bendz, L. T., Sandvik, L., et al. (2014). The plasma levels of various cytokines are increased during ongoing depression and are reduced to normal levels after recovery. Psychoneuroendocrinology 45, 77-86. doi: 10.1016/j.psyneuen.2014.03.019
51. Dantzer, R., O’Connor, J. C., Freund, G. G., Johnson, R. W., and Kelley, K. W. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat. Rev. Neurosci. 9, 46-56. doi: 10.1038/nrn2297
52. Dantzer, R., O’Connor, J. C., Lawson, M. A., and Kelley, K. W. (2011). Inflammation-associated depression: from serotonin to kynurenine. Psychoneuroendocrinology 36, 426-436. doi: 10.1016/j.psyneuen.2010.09.012
53. Dantzer, R., and Walker, A. K. (2014). Is there a role for glutamate-mediated excitotoxicity in inflammation-induced depression? J. Neural. Transm. (Vienna) 121, 925-932. doi: 10.1007/s00702-014-1187-1
54. Davis, M. J., Haley, T., Duvoisin, R. M., and Raber, J. (2012). Measures of anxiety, sensorimotor function and memoryin male and female mGluR4(-)/(-) mice. Behav. Brain Res. 229, 21-28. doi: 10.1016/j.bbr.2011.12.037
55. Dobrenis, K., Chang, H. Y., Pina-Benabou, M. H., Woodroffe, A., Lee, S. C., Rozental, R., et al. (2005). Human and mouse microglia express connexin36 and functional gap junctions are formed between rodent microglia and neurons. J. Neurosci. Res. 82, 306-315. doi: 10.1002/jnr.20650
56. Dorval, V., Nelson, P. T., and Hebert, S. S. (2013). Circulating microRNAs in Alzheimer’s disease: the search for novel biomarkers. Front. Mol. Neurosci. 6:24. doi: 10.3389/fnmol.2013.00024
57. Dowlati, Y., Herrmann, N., Swardfager, W., Liu, H., Sham, L., Reim, E. K., et al. A meta-analysis of cytokines in major depression. Biol. Psychiatry 67, 446-457. doi: 10.1016/j.biopsych.2009.09.033
58. Drago, D., Cossetti, C., Iraci, N., Gaude, E., Musco, G., Bachi, A., et al. (2013). The stem cell secretome and its role in brain repair. Biochimie 95, 2271-2285. doi: 10.1016/j.biochi.2013.06.020
59. Dubovický, M., Császár, E., Melicheraková, K., Kuniaková, M., and Rackova, L. (2014). Modulation of microglial function by the antidepressant drug venlafaxine. Interdiscip. Toxicol. 7,201-207. doi: 10.2478/intox-2014-0029
60. Dwivedi, Y. (2009). Brain-derived neurotrophic factor: role in depression and suicide. Neuropsychiatr. Dis. Treat. 5, 433-449. doi: 10.2147/ndt.s5700
61. Dwivedi, Y. (2011). Evidence demonstrating role of microRNAs in the etiopathology of major depression. J. Chem. Neuroanat. 42, 142-156. doi: 10.1016/j.jchemneu.2011.04.002
62. Dwivedi, Y. (2014). Emerging role of microRNAs in major depressive disorder: diagnosis and therapeutic implications. Dialogues Clin. Neurosci. 16, 43-61.
63. Effenberger, T., Von Der Heyde, J., Bartsch, K., Garbers, C., Schulze-Osthoff, K., Chalaris, A., et al. (2014). Senescence-associated release of transmembrane proteins involves proteolytic processing by ADAM17 and microvesicle shedding. FASEB J. 28, 4847-4856. doi: 10.1096/fj.14-254565
64. El Andaloussi, S., Lakhal, S., Mager, I., and Wood, M. J. (2013). Exosomes for targeted siRNA delivery across biological barriers. Adv. Drug Deliv. Rev. 65, 391-397. doi: 10.1016/j.addr.2012.08.008
65. El-Etr, M., Rame, M., Boucher, C., Ghoumari, A. M., Kumar, N., Liere, P., et al. (2015). Progesterone and nestorone promote myelin regeneration in chronic demyelinating lesions of corpus callosum and cerebral cortex. Glia 63,104-117. doi: 10.1002/glia.22736
66. Erny, D., Hrabe De Angelis, A. L., Jaitin, D., Wieghofer, P., Staszewski, O., David, E., et al. (2015). Host microbiota constantly control maturation and function of microglia in the CNS. Nat. Neurosci. 18, 965-977. doi: 10.1038/nn.4030
67. Etheridge, A., Lee, I., Hood, L., Galas, D., and Wang, K. (2011). Extracellular microRNA: anewsource ofbiomarkers. Mutat. Res. 717, 85-90. doi: 10.1016/j.mrfmmm.2011.03.004
68. Eugenin, E. A., Branes, M. C., Berman, J. W., and Saaez, J. C. (2003). TNF- alpha plus IFN-gamma induce connexin43 expression and formation of gap junctions between human monocytes/macrophages that enhance physiological responses. J. Immunol. 170, 1320-1328. doi: 10.4049/jimmunol.170.3.1320
69. Eyre, H., and Baune, B. T. (2012). Neuroplastic changes in depression: a role for the immune system. Psychoneuroendocrinology 37, 1397-1416. doi: 10.1016/j.psyneuen.2012.03.019
70. Falchi, A. M., Sogos, V., Saba, F., Piras, M., Congiu, T., and Piludu, M. (2013). Astrocytes shed large membrane vesicles that contain mitochondria, lipid droplets and ATP. Histochem. Cell Biol. 139, 221-231. doi: 10.1007/s00418-012-1045-x
71. Fan, H. M., Sun, X. Y., Guo, W., Zhong, A. F., Niu, W., Zhao, L., et al. (2014). Differential expression of microRNA in peripheral blood mononuclear cells as specific biomarker for major depressive disorder patients. J. Psychiatr. Res. 59, 45-52. doi: 10.1016/j.jpsychires.2014.08.007
72. Fayyad-Kazan, H., Bitar, N., Najar, M., Lewalle, P., Fayyad-Kazan, M., Badran, R., et al. (2013). Circulating miR-150 and miR-342 in plasma are novel potential biomarkers for acute myeloid leukemia. J. Transl. Med. 11:31. doi: 10.1186/1479-5876-11-31
73. Fertig, E. T., Gherghiceanu, M., and Popescu, L. M. (2014). Extracellular vesicles release by cardiac telocytes: electron microscopy and electron tomography. J. Cell. Mol. Med. 18, 1938-1943. doi: 10.1111/jcmm.12436
74. Fiandaca, M. S., Kapogiannis, D., Mapstone, M., Boxer, A., Eitan, E., Schwartz, J. B., et al. (2015). Identification ofpreclinicalAlzheimer’s disease byaprofile of pathogenic proteins in neurally derived blood exosomes: a case-control study. Alzheimers Dement. 11, 600.e1-607.e1. doi: 10.1016/j.jalz.2014.06.008
75. Fitzner, D., Schnaars, M., Van Rossum, D., Krishnamoorthy, G., Dibaj, P., Bakhti, M., et al. (2011). Selective transfer of exosomes from oligodendrocytes to microglia by macropinocytosis. J. Cell Sci. 124, 447-458. doi: 10.1242/jcs.074088
76. Frenois, F., Moreau, M., O’Connor, J., Lawson, M., Micon, C., Lestage, J., et al. Lipopolysaccharide induces delayed FosB/DeltaFosB immunostaining within the mouse extended amygdala, hippocampus and hypothalamus, that parallel the expression of depressive-like behavior. Psychoneuroendocrinology 32, 516-531. doi: 10.1016/j.psyneuen.2007.03.005
77. Frohlich, D., Kuo, W. P., Fruhbeis, 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
78. Frühbeis, C., Frohlich, D., and Kramer-Albers, E. M. (2012). Emerging roles of exosomes in neuron-glia communication. Front. Physiol. 3:119. doi: 10.3389/fphys.2012.00119
79. Frühbeis, C., Frohlich, D., Kuo, W. P., Amphornrat, J., Thilemann, S., Saab, S., et al. (2013). Neurotransmitter-triggered transfer of exosomes mediates oligodendrocyte-neuron communication. PLoS Biol. 11:e1001604. doi: 10.1371/journal.pbio.1001604
80. Frühbeis, C., Frohlich, D., Kuo, W. P., and Kramer-Albers, E. M. (2013). Extracellular vesicles as mediators of neuron-glia communication. Front. Cell. Neurosci. 7:182. doi: 10.3389/fncel.2013.00182
81. Garzetti, L., Menon, R., Finardi, A., Bergami, A., Sica, A., Martino, G., et al. (2013). Activated macrophages release microvesicles containing polarized M1 or M2 mRNAs. J. Leukoc. Biol. 95, 817-825. doi: 10.1189/jlb.0913485
82. Gemma, C., and Bachstetter, A. D. (2013). The role of microglia in adult hippocampal neurogenesis. Front. Cell. Neurosci. 7:229. doi: 10.3389/fncel.2013.00229
83. Giusti, S. A., Vogl, A. M., Brockmann, M. M., Vercelli, C. A., Rein, M. L., Trumbach, D., et al. (2014). microRNA-9 controls dendritic development by targeting REST. Elife 3:e02755. doi: 10.7554/elife.02755
84. Glebov, K., Lochner, M., Jabs, R., Lau, T., Merkel, O., Schloss, P., et al. (2015). Serotonin stimulates secretion of exosomes from microglia cells. Glia 63, 626-634. doi: 10.1002/glia.22772
85. Goldberg, D. (2010). The detection and treatment of depression in the physically ill. World Psychiatry9, 16-20. doi: 10.1002/j.2051-5545.2010.tb00256.x
86. 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
87. 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
88. 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. USA 111, 3620-3625. doi: 10.1073/pnas.1312245111
89. Gregory, R. I., and Shiekhattar, R. (2005). microRNA biogenesis and cancer. Cancer Res. 65, 3509-3512. doi: 10.1158/0008-5472.can-05-0298
90. Gu, B. J., Saunders, B. M., Petrou, S., and Wiley, J. S. (2011). P2X(7) is a scavenger receptor for apoptotic cells in the absence of its ligand, extracellular ATP. J. Immunol. 187,2365-2375. doi: 10.4049/jimmunol.1101178
91. Gupta, A., and Pulliam, L. (2014). Exosomes as mediators of neuroinflammation. J. Neuroinflammation 11:68. doi: 10.1186/1742-2094-11-68
92. Hamidi, M., Drevets, W. C., and Price, J. L. (2004). Glial reduction in amygdala in major depressive disorder is due to oligodendrocytes. Biol. Psychiatry 55, 563-569. doi: 10.1016/j.biopsych.2003.11.006
93. Hannestad, J., Dellagioia, N., Gallezot, J. D., Lim, K., Nabulsi, N., Esterlis, I., et al. The neuroinflammation marker translocator protein is not elevated in individuals with mild-to-moderate depression: a [(1)(1)C]PBR28 PET study. Brain Behav. Immun. 33, 131-138. doi: 10.1016/j.bbi.2013.06.010
94. He, Y., Zhou, Y., Xi, Q., Cui, H., Luo, T., Song, H., et al. (2012). Genetic variations in microRNA processing genes are associated with susceptibility in depression. DNA CellBiol. 31, 1499-1506. doi: 10.1089/dna.2012.1660
95. Henry, C. J., Huang, Y., Wynne, A., Hanke, M., Himler, J., Bailey, M. T., et al. (2008). Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia. J. Neuroinflammation 5:15. doi: 10.1186/1742-2094-5-15
96. Hornick, N. I., Huan, J., Doron, B., Goloviznina, N. A., Lapidus, J., Chang, H., et al. (2015). Serum exosome microRNA as a minimally-invasive early biomarker ofAML. Sci. Rep. 5:11295. doi: 10.1038/srep11295
97. Hu, G., Drescher, K. M., and Chen, X. M. (2012). Exosomal miRNAs: biological properties and therapeutic potential. Front. Genet. 3:56. doi: 10.3389/fgene.2012.00056
98. Jacobsen, J. P., Medvedev, I. O., and Caron, M. G. (2012). The 5-HT deficiency theory of depression: perspectives from a naturalistic 5-HT deficiency model, the tryptophan hydroxylase 2Arg439His knockin mouse. Philos. Trans. R. Soc. Lond. B Biol. Sci. 367, 2444-2459. doi: 10.1098/rstb.2012.0109
99. Jansen, C., Reiberger, T., Huang, J., Eischeid, H., Schierwagen, R., Mandorfer, M., et al. (2015). Circulating miRNA-122 levels are associated with hepatic necroinflammation and portal hypertension in HIV/HCV coinfection. PLoS One 10:e0116768. doi: 10.1371/journal.pone.0116768
100. Jiang, H. K., and Chang, D. M. (1999). Non-steroidal anti-inflammatory drugs with adverse psychiatric reactions: five case reports. Clin. Rheumatol. 18, 339-345. doi: 10.1007/s100670050114
101. Jo, W. K., Zhang, Y., Emrich, H. M., and Dietrich, D. E. (2015). Glia in the cytokine-mediated onset of depression: fine tuning the immune response. Front. Cell. Neurosci. 9:268. doi: 10.3389/fncel.2015.00268
102. Joshi, P., Benussi, L., Furlan, R., Ghidoni, R., and Verderio, C. (2015). Extracellular vesicles in Alzheimer’s disease: friends or foes? Focus on ap-vesicle interaction. Int. J. Mol. Sci. 16, 4800-4813. doi: 10.3390/ijms16034800
103. Joshi, P., Turola, E., Ruiz, A., Bergami, A., Libera, D. D., Benussi, L., et al. (2014). Microglia convert aggregated amyloid-p into neurotoxic forms through the shedding of microvesicles. Cell Death Differ. 21, 582-593. doi: 10.1038/cdd.2013.180
104. Kahlert, C., and Kalluri, R. (2013). Exosomes in tumor microenvironment influence cancer progression and metastasis. J. Mol. Med. (Berl). 91, 431-437. doi: 10.1007/s00109-013-1020-6
105. Kaminska, B., Gozdz, A., Zawadzka, M., Ellert-Miklaszewska, A., and Lipko, M. MAPK signal transduction underlying brain inflammation and gliosis as therapeutic target. Anat. Rec. Hoboken 292, 1902-1913. doi: 10.1002/ar.21047
106. Katsuura, S., Kuwano, Y., Yamagishi, N., Kurokawa, K., Kajita, K., Akaike, Y., et al. (2012). microRNAs miR-144/144* and miR-16 in peripheral blood are potential biomarkers for naturalistic stress in healthy Japanese medical students. Neurosci. Lett. 516, 79-84. doi: 10.1016/j.neulet.2012.03.062
107. Kettenmann, H., Hanisch, U. K., Noda, M., and Verkhratsky, A. (2011). Physiology ofmicroglia. Physiol. Rev. 91,461-553. doi: 10.1152/physrev.00011.2010
108. Khalyfa, A., and Gozal, D. (2014). Exosomal miRNAs as potential biomarkers of cardiovascular risk in children. J. Transl. Med. 12:162. doi: 10.1186/1479-587612-162
109. Kim, S. H., Bianco, N., Menon, R., Lechman, E. R., Shufesky, W. J., Morelli, A. E., et al. (2006). Exosomes derived from genetically modified DC expressing FasL are anti-inflammatory and immunosuppressive. Mol. Ther. 13, 289-300. doi: 10.1016/j.ymthe.2005.09.015
110. Kim, W. T., and Kim, W. J. (2013). microRNAs in prostate cancer. Prostate. Int. 1, 9. doi: 10.12954/pi.12011
111. Kogure, T., Lin, W. L., Yan, I. K., Braconi, C., and Patel, T. (2011). Intercellular nanovesicle-mediated microRNA transfer: a mechanism of environmental modulation of hepatocellular cancer cell growth. Hepatology 54, 1237-1248. doi: 10.1002/hep.24504
112. Konradi, C., Sillivan, S. E., and Clay, H. B. (2012). Mitochondria, oligodendrocytes and inflammation in bipolar disorder: evidence from transcriptome studies points to intriguing parallels with multiple sclerosis. Neurobiol. Dis. 45, 37-47. doi: 10.1016/j.nbd.2011.01.025
113. Kosaka, N., Iguchi, H., and Ochiya, T. (2010a). Circulating microRNA in body fluid: a new potential biomarker for cancer diagnosis and prognosis. Cancer Sci. 101, 2087-2092. doi: 10.1111/j.1349-7006.2010.01650.x
114. Kosaka, N., Iguchi, H., Yoshioka, Y., Takeshita, F., Matsuki, Y., and Ochiya, T. (2010b). Secretory mechanisms and intercellular transfer of microRNAs in living cells. J. Biol. Chem. 285, 17442-17452. doi: 10.1074/jbc.M110.107821
115. 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
116. Kreft, M., Potokar, M., Stenovec, M., Pangrsic, T., and Zorec, R. (2009). Regulated exocytosis andvesicle traffickingin astrocytes. Ann. NYAcad. Sci. 1152, 30-42. doi: 10.1111/j.1749-6632.2008.04005.x
117. Krol, J., Loedige, I., and Filipowicz, W. (2010). The widespread regulation of microRNA biogenesis, function and decay. Nat. Rev. Genet. 11, 597-610. doi: 10.1038/nrg2843
118. Ksiazek-Winiarek, D. J., Kacperska, M. J., and Glabinski, A. (2013). microRNAs as novel regulators of neuroinflammation. Mediators Inflamm. 2013:172351. doi: 10.1155/2013/172351
119. Lai, R. C., Chen, T. S., and Lim, S. K. (2011). Mesenchymal stem cell exosome: a novel stem cell-based therapy for cardiovascular disease. Regen. Med. 6, 481-492. doi: 10.2217/rme.11.35
120. Le, M. T., Xie, H., Zhou, B., Chia, P. H., Rizk, P., Um, M., et al. (2009). microRNA- 125b promotes neuronal differentiation in human cells by repressing multiple targets. Mol. Cell. Biol. 29, 5290-5305. doi: 10.1128/MCB.01694-08
121. Lee, Y., Morrison, B. M., Li, Y., Lengacher, S., Farah, M. H., Hoffman, P. N., et al. (2012). Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature 487, 443-448. doi: 10.1038/nature11314
122. Lehmann, B. D., Paine, M. S., Brooks, A. M., McCubrey, J. A., Renegar, R. H., Wang, R., et al. (2008). Senescence-associated exosome release from human prostate cancercells. CancerRes. 68,7864-7871. doi: 10.1158/0008-5472.CAN-07-6538
123. Li, B., and Sun, H. (2013). MiR-26a promotes neurite outgrowth by repressing PTEN expression. Mol. Med. Rep. 8, 676-680. doi: 10.3892/mmr.2013.1534
124. Li, Y. J., Xu, M., Gao, Z. H., Wang, Y. Q., Yue, Z., Zhang, Y. X., et al. Alterations of serum levels of BDNF-related miRNAs in patients with depression. PLoS One 8:e63648. doi: 10.1371/journal.pone.0063648
125. Lin, S., and Gregory, R. I. (2015). microRNA biogenesis pathways in cancer. Nat. Rev. Cancer 15, 321-333. doi: 10.1038/nrc3932
126. Lin, J., Li, J., Huang, B., Liu, J., Chen, X., Chen, X. M., et al. (2015). Exosomes: novel biomarkers for clinical diagnosis. Scientific World Journal 2015:657086. doi: 10.1155/2015/657086
127. Liu, H., Kaur, J., Dashtipour, K., Kinyamu, R., Ribak, C. E., and Friedman, L. K. (2003). Suppression of hippocampal neurogenesis is associated with developmental stage, number of perinatal seizure episodes and glucocorticosteroid level. Exp. Neurol. 184, 196-213. doi: 10.1016/s0014-4886(03)00207-3
128. Lo Cicero, A., Schiera, G., Proia, P., Saladino, P., Savettieri, G., Di Liegro, C. M., et al. (2011). Oligodendroglioma cells shed microvesicles which contain TRAIL as well as molecular chaperones and induce cell death in astrocytes. Int. J. Oncol. 39, 1353-1357. doi: 10.3892/ijo.2011.1160
129. Lopez, J. P., Lim, R., Cruceanu, C., Crapper, L., Fasano, C., Labonte, B., et al. miR-1202 is a primate-specific and brain-enriched microRNA involved in major depression and antidepressant treatment. Nat. Med. 20, 764-768. doi: 10.1038/nm.3582
130. Lopez-Verrilli, M. A., Picou, F., and Court, F. A. (2013). Schwann cell-derived exosomes enhance axonal regeneration in the peripheral nervous system. Glia 61, 1795-1806. doi: 10.1002/glia.22558
131. Maslanik, T., Mahaffey, L., Tannura, K., Beninson, L., Greenwood, B. N., and Fleshner, M. (2013). The inflammasome and danger associated molecular patterns (DAMPs) are implicated in cytokine and chemokine responses followingstressorexposure. Brain Behav. Immun. 28, 54-62. doi: 10.1016/j.bbi.2012.10.014
132. Mateus-Pinheiro, A., Patricio, P., Bessa, J. M., Sousa, N., and Pinto, L. (2013a). Cell genesis and dendritic plasticity: a neuroplastic pas de deux in the onset and remission from depression. Mol. Psychiatry 18, 748-750. doi: 10.1038/mp.2013.56
133. Mateus-Pinheiro, A., Pinto, L., Bessa, J. M., Morais, M., Alves, N. D., Monteiro, S., et al. (2013b). Sustained remission from depressive-like behavior depends on hippocampal neurogenesis. Transl. Psychiatry 3:e210. doi: 10.1038/tp.2012.141
134. Mathivanan, S., Fahner, C. J., Reid, G. E., and Simpson, R. J. (2012). ExoCarta 2012: database of exosomal proteins, RNA and lipids. Nucleic Acids Res. 40, D1241-D1244. doi: 10.1093/nar/gkr828
135. Matsumura, T., Sugimachi, K., Iinuma, H., Takahashi, Y., Kurashige, J., Sawada, et al. (2015). Exosomal microRNA in serum is a novel biomarker of recurrence in human colorectal cancer. Br. J. Cancer 113, 275-281. doi: 10.1038/bjc.2015.201
136. Meerson, A., Cacheaux, L., Goosens, K. A., Sapolsky, R. M., Soreq, H., and Kaufer, D. (2010). Changes in brain microRNAs contribute to cholinergic stress reactions. J. Mol. Neurosci. 40, 47-55. doi: 10.1007/s12031-009-9252-1
137. Mendell, J. T., and Olson, E. N. (2012). microRNAs in stress signaling and human disease. Cell 148, 1172-1187. doi: 10.1016/j.cell.2012.02.005
138. Metcalfe, M. J., and Figueiredo-Pereira, M. E. (2010). Relationship between tau pathology and neuroinflammation in Alzheimer’s disease. Mt. Sinai J. Med. 77, 50-58. doi: 10.1002/msj.20163
139. Miller, A. H., Maletic, V., and Raison, C. L. (2009). Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol. Psychiatry 65, 732-741. doi: 10.1016/j.biopsych.2008.11.029
140. Mishra, P. J. (2014). microRNAs as promising biomarkers in cancer diagnostics. Biomark. Res. 2:19. doi: 10.1186/2050-7771-2-19
141. Mittelbrunn, M., Gutierrez-Vazquez, C., Villarroya-Beltri, C., Gonzalez, S., Sanchez-Cabo, F., Gonzalez, M. A., et al. (2011). Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nat. Commun. 2:282. doi: 10.1038/ncomms1285
142. Mo, M. H., Chen, L., Fu, Y., Wang, W., and Fu, S. W. (2012). Cell-free circulating miRNA biomarkers in cancer. J. Cancer 3, 432-448. doi: 10.7150/jca.4919
143. Momen-Heravi, F., Balaj, L., Alian, S., Tigges, J., Toxavidis, V., Ericsson, M., et al. Alternative methods for characterization of extracellular vesicles. Front. Physiol. 3:354. doi: 10.3389/fphys.2012.00354
144. Mouillet-Richard, S., Baudry, A., Launay, J. M., and Kellermann, O. (2012). microRNAs and depression. Neurobiol. Dis. 46, 272-278. doi: 10.1016/j.nbd. 2011.12.035
145. Muller, N., and Ackenheil, M. (1998). Psychoneuroimmunology and the cytokine action in the CNS: implications for psychiatric disorders. Prog. Neuropsychopharmacol. Biol. Psychiatry 22, 1-33. doi: 10.1016/s0278-5846(97)00179-6
146. Munoz, J. L., Bliss, S. A., Greco, S. J., Ramkissoon, S. H., Ligon, K. L., and Rameshwar, P. (2013). Delivery of functional Anti-miR-9 by mesenchymal stem cell-derived exosomes to glioblastoma multiforme cells conferred chemosensitivity. Mol. Ther. NucleicAcids 2:e126. doi: 10.1038/mtna.2013.60
147. Nave, K. A. (2010). Myelination and support of axonal integrity by glia. Nature 468, 244-252. doi: 10.1038/nature09614
148. Nimmerjahn, A., Kirchhoff, F., and Helmchen, F. (2005). Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314-1318. doi: 10.1126/science.1110647
149. Noto, C., Ota, V. K., Santoro, M. L., Gouvea, E. S., Silva, P. N., Spindola, L. M., et al. Depression, cytokine and cytokine by treatment interactions modulate gene expression in antipsychotic naive first episode psychosis. Mol. Neurobiol doi: 10.1007/s12035-015-9489-3 [Epub ahead of print].
150. O’Brien, S. M., Scully, P., Fitzgerald, P., Scott, L. V., and Dinan, T. G. (2007). Plasma cytokine profiles in depressed patients who fail to respond to selective serotonin reuptake inhibitor therapy. J. Psychiatr. Res. 41, 326-331. doi: 10.1016/j.jpsychires.2006.05.013
151. O’Connor, R. M., Dinan, T. G., and Cryan, J. F. (2012). Little things on which happiness depends: microRNAs as novel therapeutic targets for the treatment of anxiety and depression. Mol. Psychiatry 17, 359-376. doi: 10.1038/mp.2011.162
152. O’Connor, J. C., Lawson, M. A., Andre, C., Moreau, M., Lestage, J., Castanon, N., et al. (2009). Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice. Mol. Psychiatry 14, 511-522. doi: 10.1038/sj.mp.4002148
153. Ohno, S., Takanashi, M., Sudo, K., Ueda, S., Ishikawa, A., Matsuyama, N., et al. Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells. Mol. Ther. 21,185-191. doi: 10.1038/mt.2012.180
154. Pallavi, P., Sagar, R., Mehta, M., Sharma, S., Subramanium, A., Shamshi, F., et al. Serum neurotrophic factors in adolescent depression: gender difference and correlation with clinical severity. J. Affect. Disord. 150, 415-423. doi: 10.1016/j.jad.2013.04.033
155. Pan, Y., Chen, X. Y., Zhang, Q. Y., and Kong, L. D. (2014). Microglial NLRP3 inflammasome activation mediates IL-1beta-related inflammation in prefrontal cortex of depressive rats. Brain Behav. Immun. 41, 90-100. doi: 10.1016/j.bbi.2014.04.007
156. Parachikova, A., Vasilevko, V., Cribbs, D. H., Laferla, F. M., and Green, K. N. (2010). Reductions in amyloid-beta-derived neuroinflammation, with minocycline, restore cognition but do not significantly affect tau hyperphosphorylation. J. Alzheimers Dis. 21, 527-542. doi: 10.3233/JAD-2010-100204
157. Paul-Savoie, E., Potvin, S., Daigle, K., Normand, E., Corbin, J. F., Gagnon, R., et al. A deficit in peripheral serotonin levels in major depressive disorder but not in chronic widespread pain. Clin. J. Pain 27, 529-534. doi: 10.1097/AJP.0b013e31820dfede
158. Peferoen, L., Kipp, M., Van Der Valk, P., Van Noort, J. M., and Amor, S. Oligodendrocyte-microglia cross-talk in the central nervous system. Immunology 141, 302-313. doi: 10.1111/imm.12163
159. Pegtel, D. M., Peferoen, L., and Amor, S. (2014). Extracellular vesicles as modulators of cell-to-cell communication in the healthy and diseased brain. Philos. Trans. R. Soc. Lond. B Biol. Sci. 369:20130516. doi: 10.1098/rstb.2013.0516
160. Phillips, A. C., Carroll, D., and Der, G. (2015). Negative life events and symptoms of depression and anxiety: stress causation and/or stress generation. Anxiety Stress Coping28, 357-371. doi: 10.1080/10615806.2015.1005078
161. Pilc, A., Chaki, S., Nowak, G., and Witkin, J. M. (2008). Mood disorders: regulation by metabotropic glutamate receptors. Biochem. Pharmacol. 75, 997-1006. doi: 10.1016/j.bcp.2007.09.021
162. 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
163. Prada, I., Furlan, R., Matteoli, M., and Verderio, C. (2013). Classical and unconventional pathways of vesicular release in microglia. Glia 61, 1003-1017. doi: 10.1002/glia.22497
164. Proia, P., Schiera, G., Mineo, M., Ingrassia, A. M., Santoro, G., Savettieri, G., et al. 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
165. Pusic, A. D., and Kraig, R. P. (2015). Phasic treatment with interferon gamma stimulates release of exosomes that protect against spreading depression. J. Interferon Cytokine Res. 35, 795-807. doi: 10.1089/jir.2015.0010
166. Pusic, A. D., Pusic, K. M., Clayton, B. L., and Kraig, R. P. (2014). IFNgamma- stimulated dendritic cell exosomes as a potential therapeutic for remyelination. J. Neuroimmunol. 266, 12-23. doi: 10.1016/j.jneuroim.2013.10.014
167. Rahman, O. A., Sasvari-Szekely, M., Szekely, A., Faludi, G., Guttman, A., and Nemoda, Z. (2010). Analysis of a polymorphic microRNA target site in the purinergic receptor P2RX7 gene. Electrophoresis 31, 1790-1795. doi: 101002/elps.200900664
168. Rajasethupathy, P., Fiumara, F., Sheridan, R., Betel, D., Puthanveettil, S. V., Russo, J. J., et al. (2009). Characterization of small RNAs in Aplysia reveals a role for miR-124 in constraining synaptic plasticity through CREB. Neuron 63, 803-817. doi: 10.1016/j.neuron.2009.05.029
169. Rajendran, L., Bali, J., Barr, M. M., Court, F. A., Kramer-Albers, E. M., Picou, F., et al. (2014). Emerging roles of extracellular vesicles in the nervous system. J. Neurosci. 34, 15482-15489. doi: 10.1523/JNEUROSCI.3258-14.2014
170. Rajkowska, G., and Miguel-Hidalgo, J. J. (2007). Gliogenesis and glial pathology in depression. CNS Neurol. Disord. Drug Targets 6, 219-233. doi: 10.2174/187152707780619326
171. Rajkowska, G., Mahajan, G., Maciag, D., Sathyanesan, M., Iyo, A. H., Moulana, M., et al. (2015). Oligodendrocyte morphometry and expression of myelin - Related mRNA in ventral prefrontal white matter in major depressive disorder. J. Psychiatr. Res. 65, 53-62. doi: 10.1016/j.jpsychires.2015.04.010
172. Raposo, G., and Stoorvogel, W. (2013). Extracellular vesicles: exosomes, microvesicles and friends. J. Cell Biol. 200, 373-383. doi: 10.1083/jcb.2012 11138
173. Ratajczak, M. Z., Kucia, M., Jadczyk, T., Greco, N. J., Wojakowski, W., Tendera, M., et al. (2012). Pivotal role of paracrine effects in stem cell therapies in regenerative medicine: can we translate stem cell-secreted paracrine factors and microvesicles into better therapeutic strategies? Leukemia 26, 1166-1173. doi: 10.1038/leu.2011.389
174. Reus, G. Z., Fries, G. R., Stertz, L., Badawy, M., Passos, I. C., Barichello, T., et al. (2015). The role of inflammation and microglial activation in the pathophysiology of psychiatric disorders. Neuroscience 300, 141-154. doi: 10.1016/j.neuroscience.2015.05.018
175. Rinaldi, A., Vincenti, S., De Vito, F., Bozzoni, I., Oliverio, A., Presutti, C., et al. (2010). Stress induces region specific alterations in microRNAs expression in mice. Behav. Brain Res. 208, 265-269. doi: 10.1016/j.bbr.2009.11.012
176. Roman, A., Kreiner, G., and Nalepa, I. (2013). Macrophages and depression - a misalliance or well-arranged marriage? Pharmacol. Rep. 65, 1663-1672. doi: 10.1016/s1734-1140(13)71528-7
177. Rota, R., Ciarapica, R., Giordano, A., Miele, L., and Locatelli, F. (2011). microRNAs in rhabdomyosarcoma: pathogenetic implications and translational potentiality. Mol. Cancer 10:120. doi: 10.1186/1476-4598-10-120
178. Rotheneichner, P., Lange, S., O’sullivan, A., Marschallinger, J., Zaunmair, P., Geretsegger, C., et al. (2014). Hippocampal neurogenesis and antidepressive therapy: shocking relations. Neural Plast. 2014:723915. doi: 10.1155/2014/723915
179. Rucker, J. J., and McGuffin, P. (2014). Chippingaway at major depressive disorder. Genome Biol. 15:421. doi: 10.1186/s13059-014-0421-3
180. Russo, I., Bubacco, L., and Greggio, E. (2012). Exosomes-associated neurodegeneration and progression of Parkinson’s disease. Am. J. Neurodegener.Dis. 1,217-225.
181. Sadallah, S., Eken, C., and Schifferli, J. A. (2011). Ectosomes as modulators of inflammation and immunity. Clin. Exp. Immunol. 163, 26-32. doi: 10.1111/j.1365-2249.2010.04271.x
182. Salgado, A. J., Sousa, J. C., Costa, B. M., Pires, A. O., Mateus-Pinheiro, A., Teixeira, F. G., et al. (2015). Mesenchymal stem cells secretome as a modulator of the neurogenic niche: basic insights and therapeutic opportunities. Front. Cell. Neurosci. 9:249. doi: 10.3389/fncel.2015.00249
183. 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(Suppl. 1), S47-S70. doi: 10.3233/JAD-132135
184. Saus, E., Soria, V., Escaramis, G., Vivarelli, F., Crespo, J. M., Kagerbauer, B., et al. (2010). Genetic variants and abnormal processing of pre-miR-182, a circadian clock modulator, in major depression patients with late insomnia. Hum. Mol. Genet. 19,4017-4025.doi: 10.1093/hmg/ddq316
185. Sbai, O., Ould-Yahoui, A., Ferhat, L., Gueye, Y., Bernard, A., Charrat, E., et al. Differential vesicular distribution and trafficking of MMP-2, MMP-9 and their inhibitors in astrocytes. Glia 58, 344-366. doi: 10.1002/glia.20927
186. Schiepers, O. J., Wichers, M. C., and Maes, M. (2005). Cytokines and major depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 29, 201-217. doi: 10.1016/j.pnpbp.2004.11.003
187. Schneider, A., and Simons, M. (2013). Exosomes: vesicular carriers forintercellular communication in neurodegenerative disorders. Cell Tissue Res. 352, 33-47. doi: 10.1007/s00441-012-1428-2
188. Schnieder, T. P., Trencevska, I., Rosoklija, G., Stankov, A., Mann, J. J., Smiley, J., et al. (2014). Microglia of prefrontal white matter in suicide. J. Neuropathol. Exp. Neurol. 73, 880-890. doi: 10.1097/NEN.0000000000000107
189. Schratt, G. M., Tuebing, F., Nigh, E. A., Kane, C. G., Sabatini, M. E., Kiebler, M., et al. (2006). A brain-specific microRNA regulates dendritic spine development. Nature 439, 283-289. doi: 10.1038/nature04367
190. Schwamborn, J. C., Berezikov, E., and Knoblich, J. A. (2009). The TRIM-NHL protein TRIM32 activates microRNAs and prevents self-renewal in mouse neural progenitors. Cell 136, 913-925. doi: 10.1016/j.cell.2008.12.024
191. Schwarzenbach, H. (2015). The clinical relevance of circulating, exosomal miRNAs as biomarkers for cancer. Expert Rev. Mol. Diagn. 15, 1159-1169. doi: 10.1586/14737159.2015.1069183
192. Serafini, G., Pompili, M., Hansen, K. F., Obrietan, K., Dwivedi, Y., Shomron, N., et al. (2014). The involvement of microRNAs in major depression, suicidal behavior and related disorders: afocus on miR-185 and miR-491-3p. Cell. Mol. Neurobiol. 34, 17-30. doi: 10.1007/s10571-013-9997-5
193. Serafini, G., Pompili, M., Innamorati, M., Giordano, G., Montebovi, F., Sher, L., et al. (2012). The role of microRNAs in synaptic plasticity, major affective disorders and suicidal behavior. Neurosci. Res. 73, 179-190. doi: 10.1016/j.neures.2012.04.001
194. Serafini, G., Rihmer, Z., and Amore, M. (2015). The role of glutamate excitotoxicity and neuroinflammation in depression and suicidal behavior: focus on microglia cells. Neuroimmunol Neuroinflamm. 2, 127-130. doi: 10.4103/2347-8659.157955
195. Shelton, R. C., Claiborne, J., Sidoryk-Wegrzynowicz, M., Reddy, R., Aschner, M., Lewis, D. A., et al. (2011). Altered expression ofgenes involved in inflammation and apoptosis in frontal cortex in major depression. Mol. Psychiatry 16, 751-762. doi: 10.1038/mp.2010.52
196. Shifrin, D. A. Jr., Demory Beckler, M., Coffey, R. J., and Tyska, M. J. (2013). Extracellular vesicles: communication, coercion and conditioning. Mol. Biol. Cell 24, 1253-1259. doi: 10.1091/mbc.E12-08-0572
197. Shtam, T. A., Kovalev, R. A., Varfolomeeva, E. Y., Makarov, E. M., Kil, Y. V., and Filatov, M. V. (2013). Exosomes are natural carriers of exogenous siRNA to human cells in vitro. Cell Commun. Signal. 11:88. doi: 10.1186/1478-811X-11-88
198. Sierra, A., Abiega, O., Shahraz, A., and Neumann, H. (2013). Janus-faced microglia: beneficial and detrimental consequences of microglial phagocytosis. Front. Cell. Neurosci. 7:6. doi: 10.3389/fncel.2013.00006
199. Smalheiser, N. R., Lugli, G., Rizavi, H. S., Torvik, V. I., Turecki, G., and Dwivedi, Y. microRNA expression is down-regulated and reorganized in prefrontal cortex of depressed suicide subjects. PLoS One 7:e33201. doi: 10.1371/journal.pone.0033201
200. Smirnova, L., Grafe, A., Seiler, A., Schumacher, S., Nitsch, R., and Wulczyn, F. G. (2005). Regulation of miRNA expression during neural cell specification. Eur. J. Neurosci. 21, 1469-1477. doi: 10.1111/j.1460-9568.2005.03978.x
201. Song, C., Halbreich, U., Han, C., Leonard, B. E., and Luo, H. (2009). Imbalance between pro- and anti-inflammatory cytokines and between Th1 and Th2 cytokines in depressed patients: the effect of electroacupuncture or fluoxetine treatment. Pharmacopsychiatry 42, 182-188. doi: 10.1055/s-0029-1202263
202. Song, C., and Wang, H. (2011). Cytokines mediated inflammation and decreased neurogenesis in animal models of depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 35, 760-768. doi: 10.1016/j.pnpbp.2010.06.020
203. Sorrells, S. F., and Sapolsky, R. M. (2007). An inflammatory review of glucocorticoid actions in the CNS. Brain Behav. Immun. 21, 259-272. doi: 10.1016/j.bbi.2006.11.006
204. Sperlagh, B., Vizi, E. S., Wirkner, K., and Illes, P. (2006). P2X7 receptors in the nervous system. Prog. Neurobiol. 78, 327-346. doi: 10.1016/j.pneurobio.2006.03.007
205. Steiner, J., Bielau, H., Brisch, R., Danos, P., Ullrich, O., Mawrin, C., et al. (2008). Immunological aspects in the neurobiology of suicide: elevated microglial density in schizophrenia and depression is associated with suicide. J. Psychiatr. Res. 42, 151-157. doi: 10.1016/j.jpsychires.2006.10.013
206. Stockmeier, C. A., and Rajkowska, G. (2004). Cellular abnormalities in depression: evidence from postmortem brain tissue. Dialogues Clin. Neurosci. 6, 185-197. doi: 10.1111/j.1582-4934.2002.tb00522.x
207. Stokes, L., Spencer, S. J., and Jenkins, T. A. (2015). Understanding the role ofP2X7 in affective disorders-are glial cells the major players? Front. Cell. Neurosci. 9:258. doi: 10.3389/fncel.2015.00258
208. Strawbridge, R., Arnone, D., Danese, A., Papadopoulos, A., Herane Vives, A., and Cleare, A. J. (2015). Inflammation and clinical response to treatment in depression: a meta-analysis. Eur. Neuropsychopharmacol. 25, 1532-1543. doi: 10.1016/j.euroneuro.2015.06.007
209. Sun, Y., Luo, Z. M., Guo, X. M., Su, D. F., and Liu, X. (2015). An updated role of microRNA-124 in central nervous system disorders: a review. Front. Cell. Neurosci. 9:193. doi: 10.3389/fncel.2015.00193
210. Szulwach, K. E., Li, X., Smrt, R. D., Li, Y., Luo, Y., Lin, L., et al. (2010). Cross talk between microRNA and epigenetic regulation in adult neurogenesis. J. Cell Biol. 189, 127-141. doi: 10.1083/jcb.200908151
211. Takeuchi, T., Suzuki, M., Fujikake, N., Popiel, H. A., Kikuchi, H., Futaki, S., et al. (2015). Intercellular chaperone transmission via exosomes contributes to maintenance of protein homeostasis at the organismal level. Proc. Natl. Acad. Sci. USA 112, E2497-E2506. doi: 10.1073/pnas.1412651112
212. Tanaka, Y., Kamohara, H., Kinoshita, K., Kurashige, J., Ishimoto, T., Iwatsuki, M., et al. (2013). Clinical impact of serum exosomal microRNA-21 as a clinical biomarker in human esophageal squamous cell carcinoma. Cancer 119, 1159-1167. doi: 10.1002/cncr.27895
213. Taylor, A. R., Robinson, M. B., Gifondorwa, D. J., Tytell, M., and Milligan, C. E. (2007). Regulation of heat shock protein 70 release in astrocytes: role of signaling kinases. Dev. Neurobiol. 67, 1815-1829. doi: 10.1002/dneu.20559
214. Terasawa, K., Ichimura, A., Sato, F., Shimizu, K., and Tsujimoto, G. (2009). Sustained activation of ERK1/2 by NGF induces microRNA-221 and 222 in PC12 cells. FEBSJ. 276, 3269-3276. doi: 10.1111/j.1742-4658.2009.07041.x
215. Thery, C., Amigorena, S., Raposo, G., and Clayton, A. (2006). Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr. Protoc. CellBiol. 3:3.22. doi: 10.1002/0471143030.cb0322s30
216. Thery, C., Zitvogel, L., and Amigorena, S. (2002). Exosomes: composition, biogenesis and function. Nat. Rev. Immunol. 2, 569-579. doi: 10.1038/nri855
217. Tomlinson, P. R., Zheng, Y., Fischer, R., Heidasch, R., Gardiner, C., Evetts, S., et al. Identification of distinct circulating exosomes in Parkinson’s disease. Ann. Clin. Transl. Neurol. 2, 353-361. doi: 10.1002/acn3.175
218. Torres-Platas, S. G., Cruceanu, C., Chen, G. G., Turecki, G., and Mechawar, N. Evidence for increased microglial priming and macrophage recruitment in the dorsal anterior cingulate white matter of depressed suicides. Brain Behav. Immun. 42, 50-59. doi: 10.1016/j.bbi.2014.05.007
219. Trajkovic, K., Hsu, C., Chiantia, S., Rajendran, L., Wenzel, D., Wieland, F., et al. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science 319, 1244-1247. doi: 10.1126/science.1153124
220. Turchinovich, A., Samatov, T. R., Tonevitsky, A. G., and Burwinkel, B. (2013). Circulating miRNAs: cell-cell communication function? Front. Genet. 4:119. doi: 10.3389/fgene.2013.00119
221. 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
222. Tynan, R. J., Beynon, S. B., Hinwood, M., Johnson, S. J., Nilsson, M., Woods, J. J., et al. (2013). Chronic stress-induced disruption of the astrocyte network is driven by structural atrophy and not loss of astrocytes. Acta Neuropathol. 126, 75-91. doi: 10.1007/s00401-013-1102-0
223. Uchida, S., Hara, K., Kobayashi, A., Funato, H., Hobara, T., Otsuki, K., et al. Early life stress enhances behavioral vulnerability to stress through the activation of REST4-mediated gene transcription in the medial prefrontal cortex of rodents. J. Neurosci. 30, 15007-15018. doi: 10.1523/JNEUROSCI.1436-10.2010
224. Valadi, H., Ekstrom, K., Bossios, A., Sjostrand, M., Lee, J. J., and Lotvall, J. O. 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
225. Van Buel, E. M., Patas, K., Peters, M., Bosker, F. J., Eisel, U. L., and Klein, H. C. Immune and neurotrophin stimulation by electroconvulsive therapy: is some inflammation needed after all? Transl. Psychiatry 5:e609. doi: 10.1038/tp.2015.100
226. Vavakova, M., Durackova, Z., and Trebaticka, J. (2015). Markers of oxidative stress and neuroprogression in depression disorder. Oxid. Med. Cell. Longev. 2015:898393. doi: 10.1155/2015/898393
227. Verderio, C., Cagnoli, C., Bergami, M., Francolini, M., Schenk, U., Colombo, A., et al. (2012a). TI-VAMP/VAMP7 is the SNARE of secretory lysosomes contributing to ATP secretion from astrocytes. Biol. Cell 104, 213-228. doi: 10.1111/boc.201100070
228. Verderio, C., Muzio, L., Turola, E., Bergami, A., Novellino, L., Ruffini, F., et al. (2012b). Myeloid microvesicles are a marker and therapeutic target for neuroinflammation. Ann. Neurol. 72, 610-624. doi: 10.1002/ana.23627
229. Vingtdeux, V., Sergeant, N., and Buee, L. (2012). Potential contribution of exosomes to the prion-like propagation of lesions in Alzheimer’s disease. Front. Physiol. 3:229. doi: 10.3389/fphys.2012.00229
230. Wahlgren, J., De L Karlson, T., Brisslert, M., Vaziri Sani, F., Telemo, E., Sunnerhagen, P., et al. (2012). Plasma exosomes can deliver exogenous short interfering RNA to monocytes and lymphocytes. Nucleic Acids Res. 40:e130. doi: 10.1093/nar/gks463
231. Walker, F. R., Nilsson, M., and Jones, K. (2013). Acute and chronic stress- induced disturbances of microglial plasticity, phenotype and function. Curr. DrugTargets 14, 1262-1276. doi: 10.2174/13894501113149990208
232. Wang, S., Cesca, F., Loers, G., Schweizer, M., Buck, F., Benfenati, F., et al. 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
233. 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
234. Wang, X., Sundquist, K., Hedelius, A., Palmer, K., Memon, A. A., and Sundquist, J. Circulating microRNA-144-5p is associated with depressive disorders. Clin.Epigenetics 7:69. doi: 10.1186/s13148-015-0099-8
235. Wan, Y., Liu, Y., Wang, X., Wu, J., Liu, K., Zhou, J., et al. (2015). Identification of differential microRNAs in cerebrospinal fluid and serum of patients with major depressive disorder. PLoS One 10:e0121975. doi: 10.1371/journal.pone.0121975
236. Warnecke-Eberz, U., Chon, S. H., Holscher, A. H., Drebber, U., and Bollschweiler, E. (2015). Exosomal onco-miRs from serum of patients with adenocarcinoma of the esophagus: comparison of miRNA profiles of exosomes and matching tumor. Tumour Biol. 36, 4643-4653. doi: 10.1007/s13277-015-3112-0
237. Weber, C. (2013). microRNAs: from basic mechanisms to clinical application in cardiovascular medicine. Arterioscler. Thromb. Vasc. Biol. 33, 168-169. doi: 10.1161/ATVBAHA.112.300920
238. Weber, M. D., Frank, M. G., Tracey, K. J., Watkins, L. R., and Maier, S. F. Stress induces the danger-associated molecular pattern HMGB-1 in the hippocampus of male Sprague Dawley rats: a priming stimulus of microglia and the NLRP3 inflammasome. J. Neurosci. 35, 316-324. doi: 10.1523/JNEUROSCI. 3561-14.2015
239. Weekman, E. M., Sudduth, T. L., Abner, E. L., Popa, G. J., Mendenhall, M. D., Brothers, H. M., et al. (2014). Transition from an M1 to a mixed neuroinflammatory phenotype increases amyloid deposition in APP/PS1 transgenic mice. J. Neuroinflammation 11:127. doi: 10.1186/1742-2094-11-127
240. Wes, P. D., Easton, A., Corradi, J., Barten, D. M., Devidze, N., DeCarr, L. B., et al. (2014). Tau overexpression impacts a neuroinflammation gene expression network perturbed in Alzheimer’s disease. PLoS One 9:e106050. doi: 10.1371/journal.pone.0106050
241. World Health and Organization. (2012). Media Centre Fact Sheet No. 369. Available online at: http://www.who.int/mediacentre/factsheets/fs369/en/
242. Wu, T. Y., Liu, L., Zhang, W., Zhang, Y., Liu, Y. Z., Shen, X. L., et al. (2015). High-mobility group box-1 was released actively and involved in LPS induced depressive-like behavior. J. Psychiatr. Res. 64, 99-106. doi: 10.1016/j.jpsychires.2015.02.016
243. Xanthos, D. N., and Sandkuhler, J. (2014). Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity. Nat. Rev. Neurosci. 15, 43-53. doi: 10.1038/nrn3617
244. Xu, D., and Tahara, H. (2013). The role of exosomes and microRNAs in senescence and aging. Adv. Drug Deliv. Rev. 65, 368-375. doi: 10.1016/j.addr.2012.07.010
245. Xu, S., Witmer, P. D., Lumayag, S., Kovacs, B., and Valle, D. (2007). microrna (miRNA) transcriptome of mouse retina and identification of a sensory organ- specific miRNA cluster. J. Biol. Chem. 282, 25053-25066. doi: 10.1074/jbc.m700501200
246. Yan, H., Fang, M., and Liu, X. Y. (2013). Role of microRNAs in stroke and poststroke depression. ScientificWorldJournal 2013:459692. doi: 10.1155/2013/459692
247. Yang, M., Chen, J., Su, F., Yu, B., Lin, L., Liu, Y., et al. (2011). Microvesicles secreted by macrophages shuttle invasion-potentiating microRNAs into breast cancer cells. Mol. Cancer 10:117. doi: 10.1186/1476-4598-10-117
248. Yang, P., Gao, Z., Zhang, H., Fang, Z., Wu, C., Xu, H., et al. (2015). Changes in proinflammatory cytokines and white matter in chronically stressed rats. Neuropsychiatr. Dis. Treat. 11, 597-607. doi: 10.2147/NDT.s78131
249. Yirmiya, R., Rimmerman, N., and Reshef, R. (2015). Depression as a microglial disease. Trends Neurosci. 38, 637-658. doi: 10.1016/j.tins.2015.08.001
250. Younger, S. T., and Corey, D. R. (2011). Transcriptional gene silencing in mammalian cells by miRNA mimics that target gene promoters. Nucleic Acids Res. 39, 5682-5691. doi: 10.1093/nar/gkr155
251. Yuyama, K., Sun, H., Mitsutake, S., and Igarashi, Y. (2012). Sphingolipid- modulated exosome secretion promotes clearance of amyloid-beta by microglia. J. Biol. Chem. 287, 10977-10989. doi: 10.1074/jbc.M111.324616
252. Yuyama, K., Sun, H., Sakai, S., Mitsutake, S., Okada, M., Tahara, H., et al. 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
253. Zhan, X., Jickling, G. C., Ander, B. P., Liu, D., Stamova, B., Cox, C., et al. (2014). Myelin injury and degraded myelin vesicles in Alzheimer’s disease. Curr.AlzheimerRes. 11,232-238. doi: 10.2174/1567205011666140131120922
254. Zheng, L. S., Kaneko, N., and Sawamoto, K. (2015). Minocycline treatment ameliorates interferon-alpha- induced neurogenic defects and depressionlike behaviors in mice. Front. Cell. Neurosci. 9:5. doi: 10.3389/fncel.2015.00005
255. Zhang, J., Li, S., Li, L., Li, M., Guo, C., Yao, J., et al. (2015). Exosome and exosomal microRNA: trafficking, sorting and function. Genomics Proteomics Bioinformatics 13, 17-24. doi: 10.1016/j.gpb.2015.02.001
256. Zhou, R., Yuan, P., Wang, Y., Hunsberger, J. G., Elkahloun, A., Wei, Y., et al. Evidence for selective microRNAs and their effectors as common longterm targets for the actions of mood stabilizers. Neuropsychopharmacology 34, 1395-1405. doi: 10.1038/npp.2008.131
257. Zhuang, X., Xiang, X., Grizzle, W., Sun, D., Zhang, S., Axtell, R. C., et al. (2011). Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain. Mol. Ther. 19, 1769-1779. doi: 10.1038/mt.2011.164
258. Zilka, N., Zilkova, M., Kazmerova, Z., Sarissky, M., Cigankova, V., and Novak, M. (2011). Mesenchymal stem cells rescue the Alzheimer’s disease cell model fromcell death induced bymisfolded truncated tau. Neuroscience 193, 330-337. doi: 10.1016/j.neuroscience.2011.06.088