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Open Access 01-12-2016 | Research

Tunneling nanotube (TNT)-mediated neuron-to neuron transfer of pathological Tau protein assemblies

Authors: Meryem Tardivel, Séverine Bégard, Luc Bousset, Simon Dujardin, Audrey Coens, Ronald Melki, Luc Buée, Morvane Colin

Published in: Acta Neuropathologica Communications | Issue 1/2016

Abstract

A given cell makes exchanges with its neighbors through a variety of means ranging from diffusible factors to vesicles. Cells use also tunneling nanotubes (TNTs), filamentous-actin-containing membranous structures that bridge and connect cells. First described in immune cells, TNTs facilitate HIV-1 transfer and are found in various cell types, including neurons. We show that the microtubule-associated protein Tau, a key player in Alzheimer’s disease, is a bona fide constituent of TNTs. This is important because Tau appears beside filamentous actin and myosin 10 as a specific marker of these fine protrusions of membranes and cytosol that are difficult to visualize. Furthermore, we observed that exogenous Tau species increase the number of TNTs established between primary neurons, thereby facilitating the intercellular transfer of Tau fibrils. In conclusion, Tau may contribute to the formation and function of the highly dynamic TNTs that may be involved in the prion-like propagation of Tau assemblies.

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Rustom A, Saffrich R, Markovic I, Walther P, Gerdes HH. Nanotubular highways for intercellular organelle transport. Science. 2004;303:1007–10.CrossRefPubMed

Gurke S, Barroso JF, Hodneland E, Bukoreshtliev NV, Schlicker O, Gerdes HH. Tunneling nanotube (TNT)-like structures facilitate a constitutive, actomyosin-dependent exchange of endocytic organelles between normal rat kidney cells. Exp Cell Res. 2008;314:3669–83. doi:10.1016/j.yexcr.2008.08.022.CrossRefPubMed

Davis DM, Sowinski S. Membrane nanotubes: dynamic long-distance connections between animal cells. Nat Rev Mol Cell Biol. 2008;9:431–6. doi:10.1038/nrm2399.CrossRefPubMed

Onfelt B, Nedvetzki S, Yanagi K, Davis DM. Cutting edge: Membrane nanotubes connect immune cells. J Immunol. 2004;173:511–1513.CrossRef

Sherer NM, Mothes W. Cytonemes and tunneling nanotubules in cell-cell communication and viral pathogenesis. Trends Cell Biol. 2008;18:414–20. doi:10.1016/j.tcb.2008.07.003.CrossRefPubMedPubMedCentral

Gousset K, et al. Prions hijack tunnelling nanotubes for intercellular spread. Nat Cell Biol. 2009;11:328–36. doi:10.1038/ncb1841.CrossRefPubMed

Sowinski S, et al. Membrane nanotubes physically connect T cells over long distances presenting a novel route for HIV-1 transmission. Nat Cell Biol. 2008;10:211–9. doi:10.1038/ncb1682.CrossRefPubMed

Gousset K, Marzo L, Commere PH, Zurzolo C. Myo10 is a key regulator of TNT formation in neuronal cells. J Cell Sci. 2013;126:4424–35. doi:10.1242/jcs.129239.CrossRefPubMed

Lachambre S, Chopard C, Beaumelle B. Preliminary characterisation of nanotubes connecting Tcells and their use by HIV-1. Biol Cell. 2014;106:394–404. doi:10.1111/boc.201400037.CrossRefPubMed

10.

Astanina K, Koch M, Jüngst C, Zumbusch A, Kiemer AK. Lipid droplets as a novel cargo of tunnelling nanotubes in endothelial cells. Sci Rep. 2015;5:11453. doi:10.1038/srep11453.CrossRefPubMedPubMedCentral

11.

Eugenin EA, Gaskill PJ, Berman JW. Tunneling nanotubes (TNT): A potential mechanism for intercellular HIV trafficking. Commun Integr Biol. 2009;2:243–4.CrossRefPubMedPubMedCentral

12.

Wang Y, Cui J, Sun X, Zhang Y. Tunneling-nanotube development in astrocytes depends on p53 activation. Cell Death Differ. 2011;18:732–42. doi:10.1038/cdd.2010.CrossRefPubMed

13.

Costanzo M, et al. Transfer of polyglutamine aggregates in neuronal cells occurs in tunneling nanotubes. J Cell Sci. 2013;126:3678–85. doi:10.1242/jcs.126086.CrossRefPubMed

14.

Ding X, et al. Exposure to ALS-FTD-CSF generates TDP-43 aggregates in glioblastoma cells through exosomes and TNTs-like structure. Oncotarget. 2015;6:24178–91.CrossRefPubMedPubMedCentral

15.

Goedert M. NEURODEGENERATION. Alzheimer’s and Parkinson’s diseases: The prion concept in relation to assembled Aβ, tau, and α-synuclein. Science. 2015;349:1255555. doi:10.1126/science.1255555.

16.

Liberski PP. Prion, prionoids and infectious amyloid. Parkinsonism Relat Disord. 2014; 20:S80–4. doi:10.1016/S1353-8020(13)70021-X.

17.

Jucker M, Walker LC. Self-propagation of pathogenic protein aggregates in neurodegenerative diseases. Nature. 2013;501:45–51. doi:10.1038/nature12481.CrossRefPubMedPubMedCentral

18.

Aguzzi A, Lakkaraju AK. Cell biology of prions and prionoids: a status report. Trends Cell Biol. 2016;26:40–51. doi:10.1016/j.tcb.2015.08.007.CrossRefPubMed

19.

Caillierez R, et al. Lentiviral delivery of the human wild-type tau protein mediates a slow and progressive neurodegenerative tau pathology in the rat brain. Mol Ther. 2013;21:1358–68. doi:10.1038/mt.2013.66.CrossRefPubMedPubMedCentral

20.

Sergeant N, et al. Dysregulation of human brain microtubule-associated tau mRNA maturation in myotonic dystrophy type 1. Hum Mol Genet. 2001;10:2143–55.CrossRefPubMed

21.

Sautiere PE, Caillet-Boudin ML, Wattez A, Delacourte A. Detection of Alzheimer-type tau proteins in okadaic acid-treated SKNSH-SY5Y neuroblastoma cells. Neurodegeneration. 1994;3:53–60.

22.

Krzewska J, Melki R. Molecular chaperones and the assembly of the prion Sup35p, an in vitro study. EMBO J. 2006;25:822–33.CrossRefPubMedPubMedCentral

23.

Gerdes HH, Bukoreshtliev NV, Barroso JF. Tunneling nanotubes: a new route for the exchange of components between animal cells. FEBS Lett. 2007;581:2194–201.CrossRefPubMed

24.

Austefjord MW, Gerdes HH, Wang X. Tunneling nanotubes: diversity in morphology and structure. Commun Integr Biol. 2014;7, e27934. doi:10.4161/cib.27934.CrossRefPubMedPubMedCentral

25.

Wittig D, Wang X, Walter C, Gerdes HH, Funk RH, Roehlecke C. Multi-level communication of human retinal pigment epithelial cells via tunneling nanotubes. PLoS One. 2012;7, e33195. doi:10.1371/journal.pone.0033195.CrossRefPubMedPubMedCentral

26.

Abounit S, Delage E, Zurzolo C. Identification and characterization of tunneling nanotubes for intercellular trafficking. Curr Protoc Cell Biol. 2015;67:12.10.1–12.10.21. doi:10.1002/0471143030.cb1210s67.CrossRef

27.

Benard M, et al. Structural and functional analysis of tunneling nanotubes (TnTs) using gCW STED and gconfocal approaches. Bio Cell. 2015;107:419–25. doi:10.1111/boc.201500004.CrossRef

28.

Chauveau A, Aucher A, Eissmann P, Vivier E, Davis DM. Membrane nanotubes facilitate long-distance interactions between natural killer cells and target cells. Proc Natl Acad Sci U S A. 2010;107:5545–50. doi:10.1073/pnas.0910074107.CrossRefPubMedPubMedCentral

29.

Comerci CJ, Mace EM, Banerjee PP, Orange JS. CD2 promotes human natural killer cell membrane nanotube formation. PLoS One. 2012;7, e47664. doi:10.1371/journal.pone.0047664.CrossRefPubMedPubMedCentral

30.

Luchetti F, et al. Fas signalling promotes intercellular communication in T cells. PLoS One. 2012;7, e35766. doi:10.1371/journal.pone.0035766.CrossRefPubMedPubMedCentral

31.

Seyed-Razavi Y, Hickey MJ, Kuffová L, McMenamin PG, Chinnery HR. Membrane nanotubes in myeloid cells in the adult mouse cornea represent a novel mode of immune cell interaction. Immunol Cell Biol. 2013;91:89–95. doi:10.1038/icb.2012.52.CrossRefPubMed

32.

Sun X, et al. Tunneling-nanotube direction determination in neurons and astrocytes. Cell Death Dis. 2012;3, e438. doi:10.1038/cddis.2012.177.CrossRefPubMedPubMedCentral

33.

Hase K, et al. M-Sec promotes membrane nanotube formation by interacting with Ral and the exocyst complex. Nat Cell Biol. 2009;11:1427–32. doi:10.1038/ncb1990.CrossRefPubMed

34.

Bukoreshtliev NV, Wang X, Hodneland E, Gurke S, Barroso JF, Gerdes HH. Selective block of tunneling nanotube (TNT) formation inhibits intercellular organelle transfer between PC12 cells. FEBS Lett. 2009;583:1481–8. doi:10.1016/j.febslet.2009.03.065.CrossRefPubMed

35.

Vallabhaneni KC, Haller H, Dumler I. Vascular smooth muscle cells initiate proliferation of mesenchymal stem cells by mitochondrial transfer via tunneling nanotubes. Stem Cells Dev. 2012;21:3104–13. doi:10.1089/scd.2011.0691.CrossRefPubMedPubMedCentral

36.

Bucciantini M, et al. Toxic effects of amyloid fibrils on cell membranes: the importance of ganglioside GM1. FASEB J. 2012;26:818–31. doi:10.1096/fj.11-189381.CrossRefPubMed

37.

Krammer C, et al. Prion protein/protein interactions: fusion with yeast Sup35p-NM modulates cytosolic PrP aggregation in mammalian cells. FASEB J. 2008;22:762–73.CrossRefPubMed

38.

Krammer C, et al. The yeast Sup35NM domain propagates as a prion in mammalian cells. Proc Natl Acad Sci U S A. 2009;106:462–7. doi:10.1073/pnas.0811571106.CrossRefPubMed

39.

Kadiu I, Gendelman HE. Human immunodeficiency virus type 1 endocytic trafficking through macrophage bridging conduits facilitates spread of infection. J Neuroimmune Pharmacol. 2011;6:658–75. doi:10.1007/s11481-011-9298-z.CrossRefPubMedPubMedCentral

40.

Marzo L, Gousset K, Zurzolo C. Multifaceted roles of tunneling nanotubes in intercellular communication. Front Physiol. 2012;3:72. doi:10.3389/fphys.2012.00072.CrossRefPubMedPubMedCentral

41.

Pantaloni D, Le Clainche C, Carlier MF. Mechanism of actin-based motility. Science. 2001;292:1502–6.CrossRefPubMed

42.

Lindwall G, Cole RD. Phosphorylation affects the ability of tau protein to promote microtubule assembly. J Biol Chem. 1984;259:5301–5.PubMed

43.

Cho J-H, Johnson GVW. Primed phosphorylation of tau at Thr231 by glycogen synthase kinase 3beta (GSK3beta) plays a critical role in regulating tau’s ability to bind and stabilize microtubules. J Neurochem. 2004;88:349–58.CrossRefPubMed

44.

Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW. A protein factor essential for microtubule assembly. Proc Natl Acad Sci U S A. 1975;72:1858–62.CrossRefPubMedPubMedCentral

45.

Iqbal K, Liu F, Gong CX. Tau and neurodegenerative disease: the story so far. Nat Rev Neurol. 2016;12:15–27. doi:10.1038/nrneurol.2015.225.CrossRefPubMed

46.

Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82:239–59.CrossRefPubMed

47.

Delacourte A, et al. The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer’s disease. Neurology. 1999;52:1158–65.CrossRefPubMed

48.

Duyckaerts C, et al. Modeling the relation between neurofibrillary tangles and intellectual status. Neurobiol Aging. 1997;18:267–73.CrossRefPubMed

49.

Qu MH, et al. Neuronal tau induces DNA conformational changes observed by atomic force microscopy. Neuroreport. 2004;15:2723–7.PubMed

50.

Sjöberg MK, Shestakova E, Mansuroglu Z, Maccioni RB, Bonnefoy E. Tau protein binds to pericentromeric DNA: a putative role for nuclear tau in nucleolar organization. J Cell Sci. 2006;119:2025–34.CrossRefPubMed

51.

Sultan A, et al. Nuclear tau, a key player in neuronal DNA protection. J Biol Chem. 2011;286:4566–75. doi:10.1074/jbc.M110.199976.CrossRefPubMed

52.

Violet M, et al. A major role for Tau in neuronal DNA and RNA protection in vivo under physiological and hyperthermic conditions. Front Cell Neurosci. 2014;8:84. doi:10.3389/fncel.2014.00084.CrossRefPubMedPubMedCentral

53.

Brandt R, Léger J, Lee G. Interaction of tau with the neural plasma membrane mediated by tau’s amino-terminal projection domain. J. Cell Biol. 1995;131:1327–40.CrossRef

54.

Pooler AM, Usardi A, Evans CJ, Philpott KL, Noble W, Hanger DP. Dynamic association of tau with neuronal membranes is regulated by phosphorylation. Neurobiol Aging. 2012;33:431.e27–38. doi:10.1016/j.neurobiolaging.2011.01.005.

55.

Ittner LM, et al. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models. Cell. 2010;142:387–97. doi:10.1016/j.cell.2010.06.036.CrossRefPubMed

56.

Mondragón-Rodríguez S, Trillaud-Doppia E, Dudilot A, Bourgeois C, Lauzon M, Leclerc N. Interaction of endogenous tau protein with synaptic proteins is regulated by N-methyl-D-aspartate receptor-dependent tau phosphorylation. J Biol Chem. 2012;287:32040–53.CrossRefPubMedPubMedCentral

57.

Pooler AM, Phillips EC, Lau DHW, Noble W, Hanger DP. Physiological release of endogenous tau is stimulated by neuronal activity. EMBO Rep. 2013;14:389–94. doi:10.1074/jbc.M112.401240.CrossRefPubMedPubMedCentral

58.

Yamada K, et al. Neuronal activity regulates extracellular tau in vivo. J Exp Med. 2014;211:387–93. doi:10.1084/jem.20131685.CrossRefPubMedPubMedCentral

59.

Johnson GV, Seubert P, Cox TM, Motter R, Brown JP, Galasko D. The tau protein in human cerebrospinal fluid in Alzheimer’s disease consists of proteolytically derived fragments. J Neurochem. 1997;68:430–3.CrossRefPubMed

60.

Plouffe V, Mohamed NV, Rivest-McGraw J, Bertrand J, Lauzon M, Leclerc N. Hyperphosphorylation and cleavage at D421 enhance tau secretion. PLoS One. 2012;7, e36873. doi:10.1371/journal.pone.0036873.CrossRefPubMedPubMedCentral

61.

Chai X, Dage JL, Citron M. Constitutive secretion of tau protein by an unconventional mechanism. Neurobiol Dis. 2012;48:356–66. doi:10.1016/j.nbd.2012.05.021.CrossRefPubMed

62.

Yamada K, et al. In vivo microdialysis reveals age dependent decrease of brain interstitial fluid tau levels in P301S human tau transgenic mice. J Neurosci. 2011;31:13110–7. doi:10.1523/JNEUROSCI.2569-11.2011.CrossRefPubMedPubMedCentral

63.

Clavaguera F, et al. Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc Natl Acad Sci U S A. 2013;110:9535–40. doi:10.1073/pnas.1301175110.CrossRefPubMedPubMedCentral

64.

Sanders DW, et al. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron. 2014;82:1271–88. doi:10.1016/j.neuron.2014.04.047.CrossRefPubMedPubMedCentral

65.

Dujardin S, et al. Ectosomes: a new mechanism for non-exosomal secretion of tau protein. PLoS One. 2014;9, e100760. doi:10.1371/journal.pone.0100760.CrossRefPubMedPubMedCentral

66.

Simón D, García-García E, Gómez-Ramos A, Falcón-Pérez JM, Díaz-Hernández M, Hernández F. Tau overexpression results in its secretion via membrane vesicles. Neurodegener Dis. 2012;10:73–5. doi:10.1159/000334915.CrossRefPubMed

67.

Saman S, et al. Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease. J Biol Chem. 2012;287:3842–9. doi:10.1074/jbc.M111.277061.CrossRefPubMed

68.

Asai H, et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci. 2015;18:1584–93. doi:10.1038/nn.4132.CrossRefPubMedPubMedCentral

69.

Takeda S, et al. Neuronal uptake and propagation of a rare phosphorylated high-molecular-weight tau derived from Alzheimer’s disease brain. Nat Commun. 2015;6:8490. doi:10.1038/ncomms9490.CrossRefPubMedPubMedCentral

70.

Elie A, et al. Tau co-organizes dynamic microtubule and actin networks. Sci Rep. 2015;5:9964. doi:10.1038/srep09964.CrossRefPubMedPubMedCentral

71.

He HJ, Wang XS, Pan R, Wang DL, Liu MN, He RQ. The proline-rich domain of tau plays a role in interactions with actin. BMC Cell Biol. 2009;10:81. doi:10.1186/1471-2121-10-81.CrossRefPubMedPubMedCentral

72.

Chinnery HR, Pearlman E, McMenamin PG. Cutting edge: membrane nanotubes in vivo: a feature of MHC class II+ cells in the mouse cornea. J Immunol. 2008;180:5779–83.CrossRefPubMedPubMedCentral

Title: Tunneling nanotube (TNT)-mediated neuron-to neuron transfer of pathological Tau protein assemblies
Authors: Meryem Tardivel
Séverine Bégard
Luc Bousset
Simon Dujardin
Audrey Coens
Ronald Melki
Luc Buée
Morvane Colin
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: Acta Neuropathologica Communications / Issue 1/2016
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/s40478-016-0386-4

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Tunneling nanotube (TNT)-mediated neuron-to neuron transfer of pathological Tau protein assemblies

Abstract

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Abstract

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