Tau is a microtubule-associated protein that aggregates in neurodegenerative disorders known as tauopathies. Recently, studies have suggested that Tau may be secreted and play a role in neural network signalling. However, once deregulated, secreted Tau may also participate in the spreading of Tau pathology in hierarchical pathways of neurodegeneration. The mechanisms underlying neuron-to-neuron Tau transfer are still unknown; given the known role of extra-cellular vesicles in cell-to-cell communication, we wondered whether these vesicles could carry secreted Tau. We found, among vesicles, that Tau is predominately secreted in ectosomes, which are plasma membrane-originating vesicles, and when it accumulates, the exosomal pathway is activated.
References
[1]
Buee L, Bussiere T, Buee-Scherrer V, Delacourte A, Hof PR (2000) Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev 33: 95–130. doi: 10.1016/s0165-0173(00)00019-9
[2]
Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82: 239–259. doi: 10.1007/bf00308809
[3]
Delacourte A, David JP, Sergeant N, Buee L, Wattez A, et al. (1999) The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer's disease. Neurology 52: 1158–1165. doi: 10.1212/wnl.52.6.1158
[4]
Verny M, Duyckaerts C, Agid Y, Hauw JJ (1996) The significance of cortical pathology in progressive supranuclear palsy. Clinico-pathological data in 10 cases. Brain 119 (Pt 4): 1123–1136. doi: 10.1093/brain/119.4.1123
[5]
Saito Y, Ruberu NN, Sawabe M, Arai T, Tanaka N, et al. (2004) Staging of argyrophilic grains: an age-associated tauopathy. J Neuropathol Exp Neurol 63: 911–918.
[6]
Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, et al. (2009) Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol 11: 909–913. doi: 10.1038/ncb1901
[7]
de Calignon A, Polydoro M, Suarez-Calvet M, William C, Adamowicz DH, et al. (2012) Propagation of tau pathology in a model of early Alzheimer's disease. Neuron 73: 685–697. doi: 10.1016/j.neuron.2011.11.033
[8]
Liu L, Drouet V, Wu JW, Witter MP, Small SA, et al. (2012) Trans-synaptic spread of tau pathology in vivo. PLoS One 7: e31302. doi: 10.1371/journal.pone.0031302
[9]
Sultan A, Nesslany F, Violet M, Begard S, Loyens A, et al. (2011) Nuclear tau, a key player in neuronal DNA protection. J Biol Chem 286: 4566–4575. doi: 10.1074/jbc.m110.199976
[10]
Brandt R, Leger J, Lee G (1995) Interaction of tau with the neural plasma membrane mediated by tau's amino-terminal projection domain. J Cell Biol 131: 1327–1340. doi: 10.1083/jcb.131.5.1327
[11]
Ittner LM, Ke YD, Delerue F, Bi M, Gladbach A, et al. (2010) Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models. Cell 142: 387–397. doi: 10.1016/j.cell.2010.06.036
[12]
Pooler AM, Phillips EC, Lau DH, Noble W, Hanger DP (2013) Physiological release of endogenous tau is stimulated by neuronal activity. EMBO Rep 14: 389–394. doi: 10.1038/embor.2013.15
[13]
Chai X, Dage JL, Citron M (2012) Constitutive secretion of tau protein by an unconventional mechanism. Neurobiol Dis 48: 356–366. doi: 10.1016/j.nbd.2012.05.021
[14]
Karch CM, Jeng AT, Goate AM (2012) Extracellular tau levels are influenced by variability in tau that is associated with tauopathies. J Biol Chem 287: 42751–42762. doi: 10.1074/jbc.m112.380642
[15]
Kim W, Lee S, Hall GF (2010) Secretion of human tau fragments resembling CSF-tau in Alzheimer's disease is modulated by the presence of the exon 2 insert. FEBS Lett 584: 3085–3088. doi: 10.1016/j.febslet.2010.05.042
[16]
Simon D, Garcia-Garcia E, Royo F, Falcon-Perez JM, Avila J (2012) Proteostasis of tau. Tau overexpression results in its secretion via membrane vesicles. FEBS Lett 586: 47–54. doi: 10.1016/j.febslet.2011.11.022
[17]
Santa-Maria I, Varghese M, Ksiezak-Reding H, Dzhun A, Wang J, et al. (2012) Paired helical filaments from Alzheimer disease brain induce intracellular accumulation of tau protein in aggresomes. J Biol Chem 287: 20522–20533. doi: 10.1074/jbc.m111.323279
[18]
Saman S, Kim W, Raya M, Visnick Y, Miro S, et al. (2012) Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease. J Biol Chem 287: 3842–3849. doi: 10.1074/jbc.m111.277061
[19]
Kfoury N, Holmes BB, Jiang H, Holtzman DM, Diamond MI (2012) Trans-cellular Propagation of Tau Aggregation by Fibrillar Species. J Biol Chem 287: 19440–19451. doi: 10.1074/jbc.m112.346072
[20]
Frost B, Jacks RL, Diamond MI (2009) Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem 284: 12845–12852. doi: 10.1074/jbc.m808759200
[21]
Kalra H, Simpson RJ, Ji H, Aikawa E, Altevogt P, et al. (2012) Vesiclepedia: a compendium for extracellular vesicles with continuous community annotation. PLoS Biol 10: e1001450. doi: 10.1371/journal.pbio.1001450
[22]
Mathivanan S, Ji H, Simpson RJ (2010) Exosomes: extracellular organelles important in intercellular communication. J Proteomics 73: 1907–1920. doi: 10.1016/j.jprot.2010.06.006
[23]
Raposo G, Nijman HW, Stoorvogel W, Liejendekker R, Harding CV, et al. (1996) B lymphocytes secrete antigen-presenting vesicles. J Exp Med 183: 1161–1172. doi: 10.1084/jem.183.3.1161
[24]
Thery C, Ostrowski M, Segura E (2009) Membrane vesicles as conveyors of immune responses. Nat Rev Immunol 9: 581–593. doi: 10.1038/nri2567
[25]
Cocucci E, Racchetti G, Meldolesi J (2009) Shedding microvesicles: artefacts no more. Trends Cell Biol 19: 43–51. doi: 10.1016/j.tcb.2008.11.003
[26]
Davizon P, Munday AD, Lopez JA (2010) Tissue factor, lipid rafts, and microparticles. Semin Thromb Hemost 36: 857–864. doi: 10.1055/s-0030-1267039
[27]
Piccin A, Murphy WG, Smith OP (2007) Circulating microparticles: pathophysiology and clinical implications. Blood Rev 21: 157–171. doi: 10.1016/j.blre.2006.09.001
[28]
Kempf M, Clement A, Faissner A, Lee G, Brandt R (1996) Tau binds to the distal axon early in development of polarity in a microtubule- and microfilament-dependent manner. J Neurosci 16: 5583–5592.
[29]
Shea TB, Spencer MJ, Beermann ML, Cressman CM, Nixon RA (1996) Calcium influx into human neuroblastoma cells induces ALZ-50 immunoreactivity: involvement of calpain-mediated hydrolysis of protein kinase C. J Neurochem 66: 1539–1549. doi: 10.1046/j.1471-4159.1996.66041539.x
[30]
Lee S, Kim W, Li Z, Hall GF (2012) Accumulation of vesicle-associated human tau in distal dendrites drives degeneration and tau secretion in an in situ cellular tauopathy model. Int J Alzheimers Dis 2012: 172837. doi: 10.1155/2012/172837
[31]
Usardi A, Pooler AM, Seereeram A, Reynolds CH, Derkinderen P, et al. (2011) Tyrosine phosphorylation of tau regulates its interactions with Fyn SH2 domains, but not SH3 domains, altering the cellular localization of tau. FEBS J 278: 2927–2937. doi: 10.1111/j.1742-4658.2011.08218.x
[32]
Doeuvre L, Plawinski L, Toti F, Angles-Cano E (2009) Cell-derived microparticles: a new challenge in neuroscience. J Neurochem 110: 457–468. doi: 10.1111/j.1471-4159.2009.06163.x
[33]
Baron M, Boulanger CM, Staels B, Tailleux A (2012) Cell-derived microparticles in atherosclerosis: biomarkers and targets for pharmacological modulation? J Cell Mol Med 16: 1365–1376. doi: 10.1111/j.1582-4934.2011.01486.x
[34]
Sergeant N, Sablonniere B, Schraen-Maschke S, Ghestem A, Maurage CA, et al. (2001) Dysregulation of human brain microtubule-associated tau mRNA maturation in myotonic dystrophy type 1. Hum Mol Genet 10: 2143–2155. doi: 10.1093/hmg/10.19.2143
[35]
Sautiere PE, Caillet-Boudin ML, Wattez A, Delacourte A (1994) Detection of Alzheimer-type tau proteins in okadaic acid-treated SKNSH-SY5Y neuroblastoma cells. Neurodegeneration 3: 53–60. doi: 10.1016/0014-5793(94)01361-4
[36]
Caillierez R, Begard S, Lecolle K, Deramecourt V, Zommer N, et al. (2013) Lentiviral Delivery of the Human Wild-type Tau Protein Mediates a Slow and Progressive Neurodegenerative Tau Pathology in the Rat Brain. Mol Ther 21: 1358–1368. doi: 10.1038/mt.2013.66
[37]
Galas MC, Dourlen P, Begard S, Ando K, Blum D, et al. (2006) The peptidylprolyl cis/trans-isomerase Pin1 modulates stress-induced dephosphorylation of Tau in neurons. Implication in a pathological mechanism related to Alzheimer disease. J Biol Chem 281: 19296–19304. doi: 10.1074/jbc.m601849200
[38]
Lecolle K, Begard S, Caillierez R, Demeyer D, Grellier E, et al. (2013) Sstr2A: a relevant target for the delivery of genes into human glioblastoma cells using fiber-modified adenoviral vectors. Gene Ther 20: 283–297. doi: 10.1038/gt.2012.39
[39]
Schraen-Maschke S, Sergeant N, Dhaenens CM, Bombois S, Deramecourt V, et al. (2008) Tau as a biomarker of neurodegenerative diseases. Biomark Med 2: 363–384. doi: 10.2217/17520363.2.4.363
[40]
Troquier L, Caillierez R, Burnouf S, Fernandez-Gomez FJ, Grosjean ME, et al. (2012) Targeting phospho-Ser422 by active Tau Immunotherapy in the THYTau22 mouse model: a suitable therapeutic approach. Curr Alzheimer Res 9: 397–405. doi: 10.2174/156720512800492503
[41]
Dujardin S, Lécolle K, Caillierez R, Bégard S, Zommer N, et al.. (2014) Neuron-to-neuron wild-type Tau protein transfer through a trans-synaptic mechanism: Relevance to sporadic Tauopathies. Acta Neuropathologica Communications In press.
[42]
Thery C, Boussac M, Veron P, Ricciardi-Castagnoli P, Raposo G, et al. (2001) Proteomic analysis of dendritic cell-derived exosomes: a secreted subcellular compartment distinct from apoptotic vesicles. J Immunol 166: 7309–7318. doi: 10.4049/jimmunol.166.12.7309
[43]
de Gassart A, Geminard C, Fevrier B, Raposo G, Vidal M (2003) Lipid raft-associated protein sorting in exosomes. Blood 102: 4336–4344. doi: 10.1182/blood-2003-03-0871
[44]
Cuervo AM, Wong ES, Martinez-Vicente M (2010) Protein degradation, aggregation, and misfolding. Mov Disord 25 Suppl 1S49–54. doi: 10.1002/mds.22718
[45]
Raposo G, Stoorvogel W (2013) Extracellular vesicles: Exosomes, microvesicles, and friends. J Cell Biol 200: 373–383. doi: 10.1083/jcb.201211138
[46]
Wang Y, Martinez-Vicente M, Kruger U, Kaushik S, Wong E, et al. (2010) Synergy and antagonism of macroautophagy and chaperone-mediated autophagy in a cell model of pathological tau aggregation. Autophagy 6: 182–183. doi: 10.4161/auto.6.1.10815
[47]
Yamada K, Cirrito JR, Stewart FR, Jiang H, Finn MB, et al. (2011) In vivo microdialysis reveals age-dependent decrease of brain interstitial fluid tau levels in P301S human tau transgenic mice. J Neurosci 31: 13110–13117. doi: 10.1523/jneurosci.2569-11.2011
[48]
Gamblin TC, Chen F, Zambrano A, Abraha A, Lagalwar S, et al. (2003) Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer's disease. Proc Natl Acad Sci U S A 100: 10032–10037. doi: 10.1073/pnas.1630428100
[49]
Wang YP, Biernat J, Pickhardt M, Mandelkow E, Mandelkow EM (2007) Stepwise proteolysis liberates tau fragments that nucleate the Alzheimer-like aggregation of full-length tau in a neuronal cell model. Proc Natl Acad Sci U S A 104: 10252–10257. doi: 10.1073/pnas.0703676104
[50]
Borroni B, Gardoni F, Parnetti L, Magno L, Malinverno M, et al. (2009) Pattern of Tau forms in CSF is altered in progressive supranuclear palsy. Neurobiol Aging 30: 34–40. doi: 10.1016/j.neurobiolaging.2007.05.009
[51]
Horowitz PM, Patterson KR, Guillozet-Bongaarts AL, Reynolds MR, Carroll CA, et al. (2004) Early N-terminal changes and caspase-6 cleavage of tau in Alzheimer's disease. J Neurosci 24: 7895–7902. doi: 10.1523/jneurosci.1988-04.2004
[52]
Plouffe V, Mohamed NV, Rivest-McGraw J, Bertrand J, Lauzon M, et al. (2012) Hyperphosphorylation and cleavage at D421 enhance tau secretion. PLoS One 7: e36873. doi: 10.1371/journal.pone.0036873
[53]
Hanisch K, Soininen H, Alafuzoff I, Hoffmann R (2010) Analysis of human tau in cerebrospinal fluid. J Proteome Res 9: 1476–1482. doi: 10.1021/pr901002t
[54]
Andrei C, Dazzi C, Lotti L, Torrisi MR, Chimini G, et al. (1999) The secretory route of the leaderless protein interleukin 1beta involves exocytosis of endolysosome-related vesicles. Mol Biol Cell 10: 1463–1475. doi: 10.1091/mbc.10.5.1463
[55]
de Calignon A, Fox LM, Pitstick R, Carlson GA, Bacskai BJ, et al. (2010) Caspase activation precedes and leads to tangles. Nature 464: 1201–1204. doi: 10.1038/nature08890
[56]
Ramcharitar J, Albrecht S, Afonso VM, Kaushal V, Bennett DA, et al. (2013) Cerebrospinal fluid tau cleaved by caspase-6 reflects brain levels and cognition in aging and Alzheimer disease. J Neuropathol Exp Neurol 72: 824–832. doi: 10.1097/nen.0b013e3182a0a39f
[57]
Ekinci FJ, Shea TB (2000) Phosphorylation of tau alters its association with the plasma membrane. Cell Mol Neurobiol 20: 497–508.
[58]
Maas T, Eidenmuller J, Brandt R (2000) Interaction of tau with the neural membrane cortex is regulated by phosphorylation at sites that are modified in paired helical filaments. J Biol Chem 275: 15733–15740. doi: 10.1074/jbc.m000389200
[59]
Diaz-Hernandez M, Gomez-Ramos A, Rubio A, Gomez-Villafuertes R, Naranjo JR, et al. (2010) Tissue-nonspecific alkaline phosphatase promotes the neurotoxicity effect of extracellular tau. J Biol Chem 285: 32539–32548. doi: 10.1074/jbc.m110.145003
[60]
Pooler AM, Usardi A, Evans CJ, Philpott KL, Noble W, et al. (2012) Dynamic association of tau with neuronal membranes is regulated by phosphorylation. Neurobiol Aging 33 431 e427–438. doi: 10.1016/j.neurobiolaging.2011.01.005
[61]
Gomez-Ramos A, Diaz-Hernandez M, Cuadros R, Hernandez F, Avila J (2006) Extracellular tau is toxic to neuronal cells. FEBS Lett 580: 4842–4850. doi: 10.1016/j.febslet.2006.07.078
[62]
Kaufman SK, Diamond MI (2013) Prion-like propagation of protein aggregation and related therapeutic strategies. Neurotherapeutics 10: 371–382. doi: 10.1007/s13311-013-0196-3
[63]
Gerson JE, Kayed R (2013) Formation and propagation of tau oligomeric seeds. Front Neurol 4: 93. doi: 10.3389/fneur.2013.00093
[64]
Castillo-Carranza DL, Sengupta U, Guerrero-Munoz MJ, Lasagna-Reeves CA, Gerson JE, et al. (2014) Passive Immunization with Tau Oligomer Monoclonal Antibody Reverses Tauopathy Phenotypes without Affecting Hyperphosphorylated Neurofibrillary Tangles. J Neurosci 34: 4260–4272. doi: 10.1523/jneurosci.3192-13.2014
[65]
Kim W, Lee S, Jung C, Ahmed A, Lee G, et al. (2010) Interneuronal transfer of human tau between Lamprey central neurons in situ. J Alzheimers Dis 19: 647–664.
[66]
Liu C, Gotz J (2013) Profiling murine tau with 0N, 1N and 2N isoform-specific antibodies in brain and peripheral organs reveals distinct subcellular localization, with the 1N isoform being enriched in the nucleus. PLoS One 8: e84849. doi: 10.1371/journal.pone.0084849
[67]
EL Andaloussi S, Mager I, Breakefield XO, Wood MJ (2013) Extracellular vesicles: biology and emerging therapeutic opportunities. Nat Rev Drug Discov 12: 347–357. doi: 10.1038/nrd3978
[68]
Choi DS, Lee J, Go G, Kim YK, Gho YS (2013) Circulating extracellular vesicles in cancer diagnosis and monitoring: an appraisal of clinical potential. Mol Diagn Ther 17: 265–271. doi: 10.1007/s40291-013-0042-7
[69]
Braak H, Del Tredici K (2011) The pathological process underlying Alzheimer's disease in individuals under thirty. Acta Neuropathol 121: 171–181. doi: 10.1007/s00401-010-0789-4