Top

Published in:

Open Access 01-04-2018 | Original Paper

Glia-to-neuron transfer of miRNAs via extracellular vesicles: a new mechanism underlying inflammation-induced synaptic alterations

Authors: Ilaria Prada, Martina Gabrielli, Elena Turola, Alessia Iorio, Giulia D’Arrigo, Roberta Parolisi, Mariacristina De Luca, Marco Pacifici, Mattia Bastoni, Marta Lombardi, Giuseppe Legname, Dan Cojoc, Annalisa Buffo, Roberto Furlan, Francesca Peruzzi, Claudia Verderio

Published in: Acta Neuropathologica | Issue 4/2018

Abstract

Recent evidence indicates synaptic dysfunction as an early mechanism affected in neuroinflammatory diseases, such as multiple sclerosis, which are characterized by chronic microglia activation. However, the mode(s) of action of reactive microglia in causing synaptic defects are not fully understood. In this study, we show that inflammatory microglia produce extracellular vesicles (EVs) which are enriched in a set of miRNAs that regulate the expression of key synaptic proteins. Among them, miR-146a-5p, a microglia-specific miRNA not present in hippocampal neurons, controls the expression of presynaptic synaptotagmin1 (Syt1) and postsynaptic neuroligin1 (Nlg1), an adhesion protein which play a crucial role in dendritic spine formation and synaptic stability. Using a Renilla-based sensor, we provide formal proof that inflammatory EVs transfer their miR-146a-5p cargo to neuron. By western blot and immunofluorescence analysis we show that vesicular miR-146a-5p suppresses Syt1 and Nlg1 expression in receiving neurons. Microglia-to-neuron miR-146a-5p transfer and Syt1 and Nlg1 downregulation do not occur when EV–neuron contact is inhibited by cloaking vesicular phosphatidylserine residues and when neurons are exposed to EVs either depleted of miR-146a-5p, produced by pro-regenerative microglia, or storing inactive miR-146a-5p, produced by cells transfected with an anti-miR-146a-5p. Morphological analysis reveals that prolonged exposure to inflammatory EVs leads to significant decrease in dendritic spine density in hippocampal neurons in vivo and in primary culture, which is rescued in vitro by transfection of a miR-insensitive Nlg1 form. Dendritic spine loss is accompanied by a decrease in the density and strength of excitatory synapses, as indicated by reduced mEPSC frequency and amplitude. These findings link inflammatory microglia and enhanced EV production to loss of excitatory synapses, uncovering a previously unrecognized role for microglia-enriched miRNAs, released in association to EVs, in silencing of key synaptic genes.

Available only for authorised users

Antonucci F, Turola E, Riganti L, Caleo M, Gabrielli M, Perrotta C, Novellino L, Clementi E, Giussani P, Viani P et al (2012) Microvesicles released from microglia stimulate synaptic activity via enhanced sphingolipid metabolism. EMBO J 31:1231–1240. https://doi.org/10.1038/emboj.2011.489 CrossRefPubMedPubMedCentral

Arroyo JD, Chevillet JR, Kroh EM, Ruf IK, Pritchard CC, Gibson DF, Mitchell PS, Bennett CF, Pogosova-Agadjanyan EL, Stirewalt DL et al (2011) Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc Natl Acad Sci USA 108:5003–5008. https://doi.org/10.1073/pnas.1019055108 CrossRefPubMedPubMedCentral

Asai H, Ikezu S, Tsunoda S, Medalla M, Luebke J, Haydar T, Wolozin B, Butovsky O, Kugler S, Ikezu T (2015) Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci 18:1584–1593. https://doi.org/10.1038/nn.4132 CrossRefPubMedPubMedCentral

Babak T, Zhang W, Morris Q, Blencowe BJ, Hughes TR (2004) Probing microRNAs with microarrays: tissue specificity and functional inference. RNA 10:1813–1819. https://doi.org/10.1261/rna.7119904 CrossRefPubMedPubMedCentral

Bartlett WP, Banker GA (1984) An electron microscopic study of the development of axons and dendrites by hippocampal neurons in culture. II. Synaptic relationships. J Neurosci Off J Soc Neurosci 4:1954–1965

Bianco F, Perrotta C, Novellino L, Francolini M, Riganti L, Menna E, Saglietti L, Schuchman EH, Furlan R, Clementi E et al (2009) Acid sphingomyelinase activity triggers microparticle release from glial cells. EMBO J 28:1043–1054. https://doi.org/10.1038/emboj.2009.45 CrossRefPubMedPubMedCentral

Bianco F, Pravettoni E, Colombo A, Schenk U, Moller T, Matteoli M, Verderio C (2005) Astrocyte-derived ATP induces vesicle shedding and IL-1 beta release from microglia. J Immunol 174:7268–7277CrossRefPubMed

Bliss TV, Collingridge GL (2013) Expression of NMDA receptor-dependent LTP in the hippocampus: bridging the divide. Mol Brain 6:5. https://doi.org/10.1186/1756-6606-6-5 CrossRefPubMedPubMedCentral

Bronevetsky Y, Villarino AV, Eisley CJ, Barbeau R, Barczak AJ, Heinz GA, Kremmer E, Heissmeyer V, McManus MT, Erle DJ et al (2013) T cell activation induces proteasomal degradation of Argonaute and rapid remodeling of the microRNA repertoire. J Exp Med 210:417–432. https://doi.org/10.1084/jem.20111717 CrossRefPubMedPubMedCentral

10.

Budnik V, Ruiz-Canada C, Wendler F (2016) Extracellular vesicles round off communication in the nervous system. Nat Rev Neurosci 17:160–172. https://doi.org/10.1038/nrn.2015.29 CrossRefPubMedPubMedCentral

11.

Butovsky O, Ziv Y, Schwartz A, Landa G, Talpalar AE, Pluchino S, Martino G, Schwartz M (2006) Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol Cell Neurosci 31:149–160. https://doi.org/10.1016/j.mcn.2005.10.006 CrossRefPubMed

12.

Centonze D, Muzio L, Rossi S, Cavasinni F, De Chiara V, Bergami A, Musella A, D’Amelio M, Cavallucci V, Martorana A et al (2009) Inflammation triggers synaptic alteration and degeneration in experimental autoimmune encephalomyelitis. J Neurosci Off J Soc Neurosci 29:3442–3452. https://doi.org/10.1523/JNEUROSCI.5804-08.2009 CrossRef

13.

Chivet M, Javalet C, Laulagnier K, Blot B, Hemming FJ, Sadoul R (2014) Exosomes secreted by cortical neurons upon glutamatergic synapse activation specifically interact with neurons. J Extracell Vesicles 3:24722. https://doi.org/10.3402/jev.v3.24722 CrossRefPubMed

14.

Christianson HC, Svensson KJ, van Kuppevelt TH, Li JP, Belting M (2013) Cancer cell exosomes depend on cell-surface heparan sulfate proteoglycans for their internalization and functional activity. Proc Natl Acad Sci USA 110:17380–17385. https://doi.org/10.1073/pnas.1304266110 CrossRefPubMedPubMedCentral

15.

Cocucci E, Meldolesi J (2015) Ectosomes and exosomes: shedding the confusion between extracellular vesicles. Trends Cell Biol 25:364–372. https://doi.org/10.1016/j.tcb.2015.01.004 CrossRefPubMed

16.

Colgan LA, Yasuda R (2014) Plasticity of dendritic spines: subcompartmentalization of signaling. Annu Rev Physiol 76:365–385. https://doi.org/10.1146/annurev-physiol-021113-170400 CrossRefPubMed

17.

Conforti L, Adalbert R, Coleman MP (2007) Neuronal death: where does the end begin? Trends Neurosci 30:159–166. https://doi.org/10.1016/j.tins.2007.02.004 CrossRefPubMed

18.

Corriden R, Insel PA (2012) New insights regarding the regulation of chemotaxis by nucleotides, adenosine, and their receptors. Purinergic Signal 8:587–598. https://doi.org/10.1007/s11302-012-9311-x CrossRefPubMedPubMedCentral

19.

Daly C, Ziff EB (1997) Post-transcriptional regulation of synaptic vesicle protein expression and the developmental control of synaptic vesicle formation. J Neurosci Off J Soc Neurosci 17:2365–2375

20.

de Candia P, De Rosa V, Casiraghi M, Matarese G (2016) Extracellular RNAs: a secret arm of immune system regulation. J Biol Chem 291:7221–7228. https://doi.org/10.1074/jbc.R115.708842 CrossRefPubMedPubMedCentral

21.

Derecki NC, Cronk JC, Lu Z, Xu E, Abbott SB, Guyenet PG, Kipnis J (2012) Wild-type microglia arrest pathology in a mouse model of Rett syndrome. Nature 484:105–109. https://doi.org/10.1038/nature10907 CrossRefPubMedPubMedCentral

22.

Ding H, Huang Z, Chen M, Wang C, Chen X, Chen J, Zhang J (2016) Identification of a panel of five serum miRNAs as a biomarker for Parkinson’s disease. Parkinsonism Relat Disord 22:68–73. https://doi.org/10.1016/j.parkreldis.2015.11.014 CrossRefPubMed

23.

Drago F, Lombardi M, Prada I, Gabrielli M, Joshi P, Cojoc D, Franck J, Vizioli J, Verderio C (2017) ATP modifies the proteome of extracellular vesicles released by microglia and influences their action on astrocytes. Front Pharmacol. https://doi.org/10.3389/fphar.2017.00910

24.

Eletto D, Russo G, Passiatore G, Del Valle L, Giordano A, Khalili K, Gualco E, Peruzzi F (2008) Inhibition of SNAP25 expression by HIV-1 Tat involves the activity of mir-128a. J Cell Physiol 216:764–770. https://doi.org/10.1002/jcp.21452 CrossRefPubMedPubMedCentral

25.

Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9:102–114. https://doi.org/10.1038/nrg2290 CrossRefPubMed

26.

Fitzner D, Schnaars M, van Rossum D, Krishnamoorthy G, Dibaj P, Bakhti M, Regen T, Hanisch UK, Simons M (2011) Selective transfer of exosomes from oligodendrocytes to microglia by macropinocytosis. J Cell Sci 124:447–458. https://doi.org/10.1242/jcs.074088 CrossRefPubMed

27.

Frohlich D, Kuo WP, Fruhbeis C, Sun JJ, Zehendner CM, Luhmann HJ, Pinto S, Toedling J, Trotter J, Kramer-Albers EM (2014) Multifaceted effects of oligodendroglial exosomes on neurons: impact on neuronal firing rate, signal transduction and gene regulation. Philos Trans R Soc Lond Ser B Biol Sci 369. https://doi.org/10.1098/rstb.2013.0510

28.

Fruhbeis C, Frohlich D, Kuo WP, Amphornrat J, Thilemann S, Saab AS, Kirchhoff F, Mobius W, Goebbels S, Nave KA et al (2013) Neurotransmitter-triggered transfer of exosomes mediates oligodendrocyte-neuron communication. PLoS Biol 11:e1001604. https://doi.org/10.1371/journal.pbio.1001604 CrossRefPubMedPubMedCentral

29.

Gabrielli M, Battista N, Riganti L, Prada I, Antonucci F, Cantone L, Matteoli M, Maccarrone M, Verderio C (2015) Active endocannabinoids are secreted on extracellular membrane vesicles. EMBO Rep 16:213–220. https://doi.org/10.15252/embr.201439668 CrossRefPubMedPubMedCentral

30.

Gao FB (2010) Context-dependent functions of specific microRNAs in neuronal development. Neural Dev 5:25. https://doi.org/10.1186/1749-8104-5-25 CrossRefPubMedPubMedCentral

31.

Goldie BJ, Dun MD, Lin M, Smith ND, Verrills NM, Dayas CV, Cairns MJ (2014) Activity-associated miRNA are packaged in Map1b-enriched exosomes released from depolarized neurons. Nucleic Acids Res 42:9195–9208. https://doi.org/10.1093/nar/gku594 CrossRefPubMedPubMedCentral

32.

Grasso M, Piscopo P, Confaloni A, Denti MA (2014) Circulating miRNAs as biomarkers for neurodegenerative disorders. Molecules 19:6891–6910. https://doi.org/10.3390/molecules19056891 CrossRefPubMed

33.

Harraz MM, Eacker SM, Wang X, Dawson TM, Dawson VL (2012) MicroRNA-223 is neuroprotective by targeting glutamate receptors. Proc Natl Acad Sci USA 109:18962–18967. https://doi.org/10.1073/pnas.1121288109 CrossRefPubMedPubMedCentral

34.

Iori V, Iyer AM, Ravizza T, Beltrame L, Paracchini L, Marchini S, Cerovic M, Hill C, Ferrari M, Zucchetti M et al (2017) Blockade of the IL-1R1/TLR4 pathway mediates disease-modification therapeutic effects in a model of acquired epilepsy. Neurobiol Dis 99:12–23. https://doi.org/10.1016/j.nbd.2016.12.007 CrossRefPubMed

35.

Iyer A, Zurolo E, Prabowo A, Fluiter K, Spliet WG, van Rijen PC, Gorter JA, Aronica E (2012) MicroRNA-146a: a key regulator of astrocyte-mediated inflammatory response. PLoS One 7:e44789. https://doi.org/10.1371/journal.pone.0044789 CrossRefPubMedPubMedCentral

36.

Jagot F, Davoust N (2016) Is it worth considering circulating microRNAs in multiple sclerosis? Front Immunol 7:129. https://doi.org/10.3389/fimmu.2016.00129 CrossRefPubMedPubMedCentral

37.

Jia LH, Liu YN (2016) Downregulated serum miR-223 servers as biomarker in Alzheimer’s disease. Cell Biochem Funct 34:233–237. https://doi.org/10.1002/cbf.3184 CrossRefPubMed

38.

Joshi P, Turola E, Ruiz A, Bergami A, Libera DD, Benussi L, Giussani P, Magnani G, Comi G, Legname G et al (2014) Microglia convert aggregated amyloid-beta into neurotoxic forms through the shedding of microvesicles. Cell Death Differ 21:582–593. https://doi.org/10.1038/cdd.2013.180 CrossRefPubMed

39.

Jovicic A, Roshan R, Moisoi N, Pradervand S, Moser R, Pillai B, Luthi-Carter R (2013) Comprehensive expression analyses of neural cell-type-specific miRNAs identify new determinants of the specification and maintenance of neuronal phenotypes. J Neurosci Off J Soc Neurosci 33:5127–5137. https://doi.org/10.1523/JNEUROSCI.0600-12.2013 CrossRef

40.

Junker A, Krumbholz M, Eisele S, Mohan H, Augstein F, Bittner R, Lassmann H, Wekerle H, Hohlfeld R, Meinl E (2009) MicroRNA profiling of multiple sclerosis lesions identifies modulators of the regulatory protein CD47. Brain J Neurol 132:3342–3352. https://doi.org/10.1093/brain/awp300 CrossRef

41.

Kadri F, Pacifici M, Wilk A, Parker-Struckhoff A, Del Valle L, Hauser KF, Knapp PE, Parsons C, Jeansonne D, Lassak A et al (2015) HIV-1-Tat protein inhibits SC35-mediated tau exon 10 inclusion through up-regulation of DYRK1A kinase. J Biol Chem 290:30931–30946. https://doi.org/10.1074/jbc.M115.675751 CrossRefPubMedPubMedCentral

42.

Kettenmann H, Kirchhoff F, Verkhratsky A (2013) Microglia: new roles for the synaptic stripper. Neuron 77:10–18. https://doi.org/10.1016/j.neuron.2012.12.023 CrossRefPubMed

43.

Kramer-Albers EM, Hill AF (2016) Extracellular vesicles: interneural shuttles of complex messages. Curr Opin Neurobiol 39:101–107. https://doi.org/10.1016/j.conb.2016.04.016 CrossRefPubMed

44.

Lioy DT, Garg SK, Monaghan CE, Raber J, Foust KD, Kaspar BK, Hirrlinger PG, Kirchhoff F, Bissonnette JM, Ballas N et al (2011) A role for glia in the progression of Rett’s syndrome. Nature 475:497–500. https://doi.org/10.1038/nature10214 CrossRefPubMedPubMedCentral

45.

Mao S, Sun Q, Xiao H, Zhang C, Li L (2015) Secreted miR-34a in astrocytic shedding vesicles enhanced the vulnerability of dopaminergic neurons to neurotoxins by targeting Bcl-2. Protein Cell 6:529–540. https://doi.org/10.1007/s13238-015-0168-y CrossRefPubMedPubMedCentral

46.

McNeill E, Van Vactor D (2012) MicroRNAs shape the neuronal landscape. Neuron 75:363–379. https://doi.org/10.1016/j.neuron.2012.07.005 CrossRefPubMedPubMedCentral

47.

Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, Peterson A, Noteboom J, O’Briant KC, Allen A et al (2008) Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci USA 105:10513–10518. https://doi.org/10.1073/pnas.0804549105 CrossRefPubMedPubMedCentral

48.

Montecalvo A, Larregina AT, Shufesky WJ, Stolz DB, Sullivan ML, Karlsson JM, Baty CJ, Gibson GA, Erdos G, Wang Z et al (2012) Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes. Blood 119:756–766. https://doi.org/10.1182/blood-2011-02-338004 CrossRefPubMedPubMedCentral

49.

Morris GP, Clark IA, Zinn R, Vissel B (2013) Microglia: a new frontier for synaptic plasticity, learning and memory, and neurodegenerative disease research. Neurobiol Learn Mem 105:40–53. https://doi.org/10.1016/j.nlm.2013.07.002 CrossRefPubMed

50.

Mulcahy LA, Pink RC, Carter DR (2014) Routes and mechanisms of extracellular vesicle uptake. J Extracell Vesicles 3. https://doi.org/10.3402/jev.v3.24641

51.

Pacifici M, Delbue S, Ferrante P, Jeansonne D, Kadri F, Nelson S, Velasco-Gonzalez C, Zabaleta J, Peruzzi F (2013) Cerebrospinal fluid miRNA profile in HIV-encephalitis. J Cell Physiol 228:1070–1075. https://doi.org/10.1002/jcp.24254 CrossRefPubMedPubMedCentral

52.

Pacifici M, Delbue S, Kadri F, Peruzzi F (2014) Cerebrospinal fluid MicroRNA profiling using quantitative real time PCR. J Vis Exp JoVE 83:e51172. https://doi.org/10.3791/51172

53.

Paolicelli RC, Ferretti MT (2017) Function and dysfunction of microglia during brain development: consequences for synapses and neural circuits. Front Synapt Neurosci 9:9. https://doi.org/10.3389/fnsyn.2017.00009 CrossRef

54.

Parkhurst CN, Yang G, Ninan I, Savas JN, Yates JR 3rd, Lafaille JJ, Hempstead BL, Littman DR, Gan WB (2013) Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 155:1596–1609. https://doi.org/10.1016/j.cell.2013.11.030 CrossRefPubMedPubMedCentral

55.

Pascual O, Achour SB, Rostaing P, Triller A, Bessis A (2012) Microglia activation triggers astrocyte-mediated modulation of excitatory neurotransmission. Proc Natl Acad Sci USA 109:E197–E205. https://doi.org/10.1073/pnas.1111098109 CrossRefPubMed

56.

Patton JG, Franklin JL, Weaver AM, Vickers K, Zhang B, Coffey RJ, Ansel KM, Blelloch R, Goga A, Huang B et al (2015) Biogenesis, delivery, and function of extracellular RNA. J Extracell Vesicles 4:27494. https://doi.org/10.3402/jev.v4.27494 CrossRefPubMed

57.

Planche V, Ruet A, Coupe P, Lamargue-Hamel D, Deloire M, Pereira B, Manjon JV, Munsch F, Moscufo N, Meier DS et al (2016) Hippocampal microstructural damage correlates with memory impairment in clinically isolated syndrome suggestive of multiple sclerosis. Mult Scler 23:1214. https://doi.org/10.1177/1352458516675750 CrossRefPubMed

58.

Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, Fujihara K, Havrdova E, Hutchinson M, Kappos L et al (2011) Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 69:292–302. https://doi.org/10.1002/ana.22366 CrossRefPubMedPubMedCentral

59.

Prada I, Amin L, Furlan R, Legname G, Verderio C, Cojoc D (2016) A new approach to follow a single extracellular vesicle-cell interaction using optical tweezers. Biotechniques 60:35–41. https://doi.org/10.2144/000114371 CrossRefPubMed

60.

Properzi F, Ferroni E, Poleggi A, Vinci R (2015) The regulation of exosome function in the CNS: implications for neurodegeneration. Swiss Med Wkly 145:w14204. https://doi.org/10.4414/smw.2015.14204 PubMed

61.

Reddy PH, Tonk S, Kumar S, Vijayan M, Kandimalla R, Kuruva CS, Reddy AP (2017) A critical evaluation of neuroprotective and neurodegenerative MicroRNAs in Alzheimer’s disease. Biochem Biophys Res Commun 483:1156–1165. https://doi.org/10.1016/j.bbrc.2016.08.067 CrossRefPubMed

62.

Riganti L, Antonucci F, Gabrielli M, Prada I, Giussani P, Viani P, Valtorta F, Menna E, Matteoli M, Verderio C (2016) Sphingosine-1-Phosphate (S1P) impacts presynaptic functions by regulating synapsin I localization in the presynaptic compartment. J Neurosci 36:4624–4634. https://doi.org/10.1523/JNEUROSCI.3588-15.2016 CrossRefPubMed

63.

Rocca MA, Amato MP, De Stefano N, Enzinger C, Geurts JJ, Penner IK, Rovira A, Sumowski JF, Valsasina P, Filippi M et al (2015) Clinical and imaging assessment of cognitive dysfunction in multiple sclerosis. Lancet Neurol 14:302–317. https://doi.org/10.1016/S1474-4422(14)70250-9 CrossRefPubMed

64.

Rom S, Rom I, Passiatore G, Pacifici M, Radhakrishnan S, Del Valle L, Pina-Oviedo S, Khalili K, Eletto D, Peruzzi F (2010) CCL8/MCP-2 is a target for mir-146a in HIV-1-infected human microglial cells. FASEB J Off Publ Feder Am Soc Exp Biol 24:2292–2300. https://doi.org/10.1096/fj.09-143503

65.

Rossi S, Muzio L, De Chiara V, Grasselli G, Musella A, Musumeci G, Mandolesi G, De Ceglia R, Maida S, Biffi E et al (2011) Impaired striatal GABA transmission in experimental autoimmune encephalomyelitis. Brain Behav Immun 25:947–956. https://doi.org/10.1016/j.bbi.2010.10.004 CrossRefPubMed

66.

Saba R, Storchel PH, Aksoy-Aksel A, Kepura F, Lippi G, Plant TD, Schratt GM (2012) Dopamine-regulated microRNA MiR-181a controls GluA2 surface expression in hippocampal neurons. Mol Cell Biol 32:619–632. https://doi.org/10.1128/MCB.05896-11 CrossRefPubMedPubMedCentral

67.

Schonrock N, Ke YD, Humphreys D, Staufenbiel M, Ittner LM, Preiss T, Gotz J (2010) Neuronal microRNA deregulation in response to Alzheimer’s disease amyloid-beta. PLoS One 5:e11070. https://doi.org/10.1371/journal.pone.0011070 CrossRefPubMedPubMedCentral

68.

Schratt G (2009) microRNAs at the synapse. Nat Rev Neurosci 10:842–849. https://doi.org/10.1038/nrn2763 CrossRefPubMed

69.

Sempere LF, Freemantle S, Pitha-Rowe I, Moss E, Dmitrovsky E, Ambros V (2004) Expression profiling of mammalian microRNAs uncovers a subset of brain-expressed microRNAs with possible roles in murine and human neuronal differentiation. Genome Biol 5:R13. https://doi.org/10.1186/gb-2004-5-3-r13 CrossRefPubMedPubMedCentral

70.

Shipman SL, Nicoll RA (2012) Dimerization of postsynaptic neuroligin drives synaptic assembly via transsynaptic clustering of neurexin. Proc Natl Acad Sci USA 109:19432–19437. https://doi.org/10.1073/pnas.1217633109 CrossRefPubMedPubMedCentral

71.

Shipton OA, Paulsen O (2014) GluN2A and GluN2B subunit-containing NMDA receptors in hippocampal plasticity. Philos Trans R Soc Lond B Biol Sci 369:20130163. https://doi.org/10.1098/rstb.2013.0163 CrossRefPubMedPubMedCentral

72.

Shurtleff MJ, Temoche-Diaz MM, Karfilis KV, Ri S, Schekman R (2016) Y-box protein 1 is required to sort microRNAs into exosomes in cells and in a cell-free reaction. eLife 5. https://doi.org/10.7554/elife.19276

73.

Tong L, Prieto GA, Kramar EA, Smith ED, Cribbs DH, Lynch G, Cotman CW (2012) Brain-derived neurotrophic factor-dependent synaptic plasticity is suppressed by interleukin-1beta via p38 mitogen-activated protein kinase. J Neurosci Off J Soc Neurosci 32:17714–17724. https://doi.org/10.1523/JNEUROSCI.1253-12.2012 CrossRef

74.

Tremblay ME, Stevens B, Sierra A, Wake H, Bessis A, Nimmerjahn A (2011) The role of microglia in the healthy brain. J Neurosci Off J Soc Neurosci 31:16064–16069. https://doi.org/10.1523/JNEUROSCI.4158-11.2011 CrossRef

75.

van Dongen HM, Masoumi N, Witwer KW, Pegtel DM (2016) Extracellular vesicles exploit viral entry routes for cargo delivery. Microbiol Mol Biol Rev MMBR 80:369–386. https://doi.org/10.1128/MMBR.00063-15 CrossRefPubMed

76.

van Scheppingen J, Iyer AM, Prabowo AS, Muhlebner A, Anink JJ, Scholl T, Feucht M, Jansen FE, Spliet WG, Krsek P et al (2016) Expression of microRNAs miR21, miR146a, and miR155 in tuberous sclerosis complex cortical tubers and their regulation in human astrocytes and SEGA-derived cell cultures. Glia 64:1066–1082. https://doi.org/10.1002/glia.22983 PubMed

77.

Vella LJ, Hill AF, 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. https://doi.org/10.3390/ijms17020173 CrossRefPubMedPubMedCentral

78.

Verderio C, Muzio L, Turola E, Bergami A, Novellino L, Ruffini F, Riganti L, Corradini I, Francolini M, Garzetti L et al (2012) Myeloid microvesicles are a marker and therapeutic target for neuroinflammation. Ann Neurol 72:610–624. https://doi.org/10.1002/ana.23627 CrossRefPubMed

79.

Viviani B, Bartesaghi S, Gardoni F, Vezzani A, Behrens MM, Bartfai T, Binaglia M, Corsini E, Di Luca M, Galli CL et al (2003) Interleukin-1beta enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases. J Neurosci Off J Soc Neurosci 23:8692–8700

80.

Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J (2009) Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci Off J Soc Neurosci 29:3974–3980. https://doi.org/10.1523/JNEUROSCI.4363-08.2009 CrossRef

81.

Weber A, Wasiliew P, Kracht M (2010) Interleukin-1 (IL-1) pathway. Sci Signal 3:cm1. https://doi.org/10.1126/scisignal.3105cm1 PubMed

82.

Wu Y, Dissing-Olesen L, MacVicar BA, Stevens B (2015) Microglia: dynamic mediators of synapse development and plasticity. Trends Immunol 36:605–613. https://doi.org/10.1016/j.it.2015.08.008 CrossRefPubMedPubMedCentral

83.

Xiao C, Rajewsky K (2009) MicroRNA control in the immune system: basic principles. Cell 136:26–36. https://doi.org/10.1016/j.cell.2008.12.027 CrossRefPubMed

84.

Yuan J, Ge H, Liu W, Zhu H, Chen Y, Zhang X, Yang Y, Yin Y, Chen W, Wu W et al (2017) M2 microglia promotes neurogenesis and oligodendrogenesis from neural stem/progenitor cells via the PPARgamma signaling pathway. Oncotarget 8:19855–19865. https://doi.org/10.18632/oncotarget.15774 PubMedPubMedCentral

85.

Zaqout S, Kaindl AM (2016) Golgi–Cox staining step by step. Front Neuroanat 10:38. https://doi.org/10.3389/fnana.2016.00038 CrossRefPubMedPubMedCentral

86.

Zhang S, Yu M, Guo Q, Li R, Li G, Tan S, Li X, Wei Y, Wu M (2015) Annexin A2 binds to endosomes and negatively regulates TLR4-triggered inflammatory responses via the TRAM-TRIF pathway. Sci Rep 5:15859. https://doi.org/10.1038/srep15859 CrossRefPubMedPubMedCentral

Title: Glia-to-neuron transfer of miRNAs via extracellular vesicles: a new mechanism underlying inflammation-induced synaptic alterations
Authors: Ilaria Prada
Martina Gabrielli
Elena Turola
Alessia Iorio
Giulia D’Arrigo
Roberta Parolisi
Mariacristina De Luca
Marco Pacifici
Mattia Bastoni
Marta Lombardi
Giuseppe Legname
Dan Cojoc
Annalisa Buffo
Roberto Furlan
Francesca Peruzzi
Claudia Verderio
Publication date: 01-04-2018
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 4/2018
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-017-1803-x

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Glia-to-neuron transfer of miRNAs via extracellular vesicles: a new mechanism underlying inflammation-induced synaptic alterations

Abstract

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2018

5-Hydroxymethylcytosine preferentially targets genes upregulated in isocitrate dehydrogenase 1 mutant high-grade glioma

The DNA methylome of DDR genes and benefit from RT or TMZ in IDH mutant low-grade glioma treated in EORTC 22033

Integrated neurodegenerative disease autopsy diagnosis

T lymphocytes facilitate brain metastasis of breast cancer by inducing Guanylate-Binding Protein 1 expression

The referee who agrees to review and never responds again (NERO): a series of 37 cases of an emerging entity

cIMPACT-NOW update 2: diagnostic clarifications for diffuse midline glioma, H3 K27M-mutant and diffuse astrocytoma/anaplastic astrocytoma, IDH-mutant