Please use this identifier to cite or link to this item: http://hdl.handle.net/1942/23690
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dc.contributor.authorZhou, Lujia-
dc.contributor.authorMcInnes, Joseph-
dc.contributor.authorWeirda, Keimpe-
dc.contributor.authorHolt, Matthew-
dc.contributor.authorHerrmann, Abigail G.-
dc.contributor.authorJackson, Rosemary J.-
dc.contributor.authorWang, Yu-Chun-
dc.contributor.authorSwerts, Jef-
dc.contributor.authorBeyens, Jelle-
dc.contributor.authorMiskiewicz, Katarzyna-
dc.contributor.authorVilain, Sven-
dc.contributor.authorDEWACHTER, Ilse-
dc.contributor.authorMoechars, Diederik-
dc.contributor.authorDe Strooper, Bart-
dc.contributor.authorSpires-Jones, Tara L.-
dc.contributor.authorDe Wit, Joris-
dc.contributor.authorVerstreken, Patrik-
dc.date.accessioned2017-05-17T08:01:48Z-
dc.date.available2017-05-17T08:01:48Z-
dc.date.issued2017-
dc.identifier.citationNature Communications, 11(8), p. 1-13 (Art N° 15295)-
dc.identifier.issn2041-1723-
dc.identifier.urihttp://hdl.handle.net/1942/23690-
dc.description.abstractTau is implicated in more than 20 neurodegenerative diseases, including Alzheimer’s disease. Under pathological conditions, Tau dissociates from axonal microtubules and missorts to pre- and postsynaptic terminals. Patients suffer from early synaptic dysfunction prior to Tau aggregate formation, but the underlying mechanism is unclear. Here we show that pathogenic Tau binds to synaptic vesicles via its N-terminal domain and interferes with presynaptic functions, including synaptic vesicle mobility and release rate, lowering neurotransmission in fly and rat neurons. Pathological Tau mutants lacking the vesicle binding domain still localize to the presynaptic compartment but do not impair synaptic function in fly neurons. Moreover, an exogenously applied membrane-permeable peptide that competes for Tau-vesicle binding suppresses Tau-induced synaptic toxicity in rat neurons. Our work uncovers a presynaptic role of Tau that may be part of the early pathology in various Tauopathies and could be exploited therapeutically.-
dc.description.sponsorshipWe thank Colin Smith and Matthew Frosch for access to human tissue. We thank lab members of the Verstreken laboratory for helpful discussions, and Kristel Vennekens and An Snellinx for technical support. Support was provided by an ERC Starting Grant (260678), ERC Consolidator grant (646671), the Instituut voor Wetenschap en Technologie (IWT O&O grant), the Interuniversity Attraction Pole program by BELSPO, the research fund KU Leuven, a Methusalem grant of the Flemish government and VIB, Leuvens Universiteitsfonds (LUF) Opening the Future grant, and a Belgian-American Educational Foundation fellowship to J.M. T.S.-J., A.H. and R.J.J. receive funding from Alzheimer's Research UK, an anonymous foundation, and a Welcome Trust Institutional strategic support grant.-
dc.language.isoen-
dc.rightsThis work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (c) The Author(s) 2017-
dc.subject.otherAlzheimer's disease; Tauopathies; Tau; presynaptic-
dc.titleTau association with synaptic vesicles causes presynaptic dysfunction-
dc.typeJournal Contribution-
dc.identifier.epage13-
dc.identifier.issue8-
dc.identifier.spage1-
dc.identifier.volume11-
local.bibliographicCitation.jcatA1-
dc.description.notesVerstreken, P (reprint author), VIB KU Leuven Ctr Brain & Dis Res, B-3000 Leuven, Belgium. patrik.verstreken@cme.vib-kuleuven.be-
dc.relation.referencesReferences 1. Morris, M., Maeda, S., Vossel, K. & Mucke, L. The many faces of tau. Neuron 70, 410–426 (2011). 2. Ballatore, C., Lee, V. M. & Trojanowski, J. Q. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat. Rev. Neurosci. 8, 663–672 (2007). 3. Wang, Y. & Mandelkow, E. Tau in physiology and pathology. Nat. Rev. Neurosci. 17, 22–35 (2016). 4. Kwok, J. B. et al. Tau haplotypes regulate transcription and are associated with Parkinson’s disease. Ann. Neurol. 55, 329–334 (2004). 5. Refenes, N. et al. Role of the H1 haplotype of microtubule-associated protein tau (MAPT) gene in Greek patients with Parkinson’s disease. BMC Neurol. 9, 26 (2009). 6. Allen, M. et al. Association of MAPT haplotypes with Alzheimer’s disease risk and MAPT brain gene expression levels. Alzheimers Res. Ther. 6, 39 (2014). 7. Liu, T. et al. Amyloid-beta-induced toxicity of primary neurons is dependent upon differentiation-associated increases in tau and cyclin-dependent kinase 5 expression. J. Neurochem. 88, 554–563 (2004). 8. Rapoport, M., Dawson, H. N., Binder, L. I., Vitek, M. P. & Ferreira, A. Tau is essential to beta -amyloid-induced neurotoxicity. Proc. Natl Acad. Sci. USA 99, 6364–6369 (2002). 9. Nussbaum, J. M. et al. Prion-like behaviour and tau-dependent cytotoxicity of pyroglutamylated amyloid-b. Nature 485, 651–655 (2012). 10. Roberson, E. D. et al. Reducing endogenous tau ameliorates amyloid betainduced deficits in an Alzheimer’s disease mouse model. Science 316, 750–754 (2007). 11. Holth, J. K. et al. Tau loss attenuates neuronal network hyperexcitability in mouse and Drosophila genetic models of epilepsy. J. Neurosci. 33, 1651–1659 (2013). 12. DeVos, S. L. et al. Antisense reduction of tau in adult mice protects against seizures. J. Neurosci. 33, 12887–12897 (2013). 13. Masliah, E. et al. Altered expression of synaptic proteins occurs early during progression of Alzheimer’s disease. Neurology 56, 127–129 (2001). 14. Bellucci, A., Navarria, L., Zaltieri, M., Missale, C. & Spano, P. a-Synuclein synaptic pathology and its implications in the development of novel therapeutic approaches to cure Parkinson’s disease. Brain Res. 1432, 95–113 (2012). 15. Milnerwood, A. J. & Raymond, L. A. Early synaptic pathophysiology in neurodegeneration: insights from Huntington’s disease. Trends Neurosci. 33, 513–523 (2010). 16. Scheff, S. W., Price, D. A., Schmitt, F. A. & Mufson, E. J. Hippocampal synaptic loss in early Alzheimer’s disease and mild cognitive impairment. Neurobiol. Aging 27, 1372–1384 (2006). 17. Yoshiyama, Y. et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53, 337–351 (2007). 18. Crimins, J. L., Rocher, A. B. & Luebke, J. I. Electrophysiological changes precede morphological changes to frontal cortical pyramidal neurons in the rTg4510 mouse model of progressive tauopathy. Acta Neuropathol. 124, 777–795 (2012). 19. Polydoro, M. et al. Soluble pathological tau in the entorhinal cortex leads to presynaptic deficits in an early Alzheimer’s disease model. Acta Neuropathol. 127, 257–270 (2014). 20. Sydow, A. et al. Tau-induced defects in synaptic plasticity, learning, and memory are reversible in transgenic mice after switching off the toxic Tau mutant. J. Neurosci. 31, 2511–2525 (2011). 21. Hoover, B. R. et al. Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron 68, 1067–1081 (2010). 22. Erez, H., Shemesh, O. A. & Spira, M. E. Rescue of tau-induced synaptic transmission pathology by paclitaxel. Front. Cell Neurosci. 8, 34 (2014). 23. Menkes-Caspi, N. et al. Pathological tau disrupts ongoing network activity. Neuron 85, 959–966 (2015). 24. Santacruz, K. et al. Tau suppression in a neurodegenerative mouse model improves memory function. Science 309, 476–481 (2005). 25. Hong, M. et al. Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17. Science 282, 1914–1917 (1998). 26. Fein, J. A. et al. Co-localization of amyloid beta and tau pathology in Alzheimer’s disease synaptosomes. Am. J. Pathol. 172, 1683–1692 (2008). 27. Sokolow, S. et al. Pre-synaptic C-terminal truncated tau is released from cortical synapses in Alzheimer’s disease. J. Neurochem. 133, 368–379 (2015). 28. Henkins, K. M. et al. Extensive p-tau pathology and SDS-stable p-tau oligomers in Alzheimer’s cortical synapses. Brain Pathol. 22, 826–833 (2012). 29. Tai, H. C. et al. The synaptic accumulation of hyperphosphorylated tau oligomers in Alzheimer disease is associated with dysfunction of the ubiquitinproteasome system. Am. J. Pathol. 181, 1426–1435 (2012). 30. Sahara, N., Murayama, M., Higuchi, M., Suhara, T. & Takashima, A. Biochemical distribution of Tau protein in synaptosomal fraction of transgenic mice expressing human P301L Tau. Front. Neurol. 5, 26 (2014). 31. Harris, J. A. et al. Human P301L-mutant tau expression in mouse entorhinalhippocampal network causes tau aggregation and presynaptic pathology but no cognitive deficits. PLoS ONE 7, e45881 (2012).32. Ittner, L. M. et al. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models. Cell 142, 387–397 (2010). 33. Lloyd, T. E. et al. A genome-wide search for synaptic vesicle cycle proteins in Drosophila. Neuron 26, 45–50 (2000). 34. Hadley, D. et al. Patterns of sequence conservation in presynaptic neural genes. Genome Biol. 7, R105 (2006). 35. Dias-Santagata, D., Fulga, T. A., Duttaroy, A. & Feany, M. B. Oxidative stress mediates tau-induced neurodegeneration in Drosophila. J. Clin. Invest. 117, 236–245 (2007). 36. Frost, B., Hemberg, M., Lewis, J. & Feany, M. B. Tau promotes neurodegeneration through global chromatin relaxation. Nat. Neurosci. 17, 357–366 (2014). 37. Khurana, V. et al. TOR-mediated cell-cycle activation causes neurodegeneration in a Drosophila tauopathy model. Curr. Biol. 16, 230–241 (2006). 38. Wittmann, C. W. et al. Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles. Science 293, 711–714 (2001). 39. Kawasaki, F., Hazen, M. & Ordway, R. W. Fast synaptic fatigue in shibire mutants reveals a rapid requirement for dynamin in synaptic vesicle membrane trafficking. Nat. Neurosci. 3, 859–860 (2000). 40. Verstreken, P. et al. Endophilin mutations block clathrin-mediated endocytosis but not neurotransmitter release. Cell 109, 101–112 (2002). 41. Saheki, Y. & De Camilli, P. Synaptic vesicle endocytosis. Cold Spring Harb. Perspect. Biol. 4, a005645 (2012). 42. Sara, Y., Mozhayeva, M. G., Liu, X. & Kavalali, E. T. Fast vesicle recycling supports neurotransmission during sustained stimulation at hippocampal synapses. J. Neurosci. 22, 1608–1617 (2002). 43. Verstreken, P. et al. Synaptic mitochondria are critical for mobilization of reserve pool vesicles at Drosophila neuromuscular junctions. Neuron 47, 365–378 (2005). 44. Alabi, A. A. & Tsien, R. W. Synaptic vesicle pools and dynamics. Cold Spring Harb. Perspect. Biol. 4, a013680 (2012). 45. Ferna´ndez-Alfonso, T. & Ryan, T. A. The kinetics of synaptic vesicle pool depletion at CNS synaptic terminals. Neuron 41, 943–953 (2004). 46. Gaffield, M. A., Rizzoli, S. O. & Betz, W. J. Mobility of synaptic vesicles in different pools in resting and stimulated frog motor nerve terminals. Neuron 51, 317–325 (2006). 47. Miesenbo¨ck, G., De Angelis, D. A. & Rothman, J. E. Visualizing secretion and synaptic transmission with pH-sensitive green fluorescent proteins. Nature 394, 192–195 (1998). 48. Fulga, T. A. et al. Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo. Nat. Cell Biol. 9, 139–148 (2007). 49. He, H. J. et al. The proline-rich domain of tau plays a role in interactions with actin. BMC Cell Biol. 10, 81 (2009). 50. Shupliakov, O., Haucke, V. & Pechstein, A. How synapsin I may cluster synaptic vesicles. Semin. Cell Dev. Biol. 22, 393–399 (2011). 51. Steinhilb, M. L., Dias-Santagata, D., Fulga, T. A., Felch, D. L. & Feany, M. B. Tau phosphorylation sites work in concert to promote neurotoxicity in vivo. Mol. Biol. Cell 18, 5060–5068 (2007). 52. Bekkers, J. M. & Stevens, C. F. Excitatory and inhibitory autaptic currents in isolated hippocampal neurons maintained in cell culture. Proc. Natl Acad. Sci. USA 88, 7834–7838 (1991). 53. Chouhan, A. K. et al. Uncoupling neuronal death and dysfunction in Drosophila models of neurodegenerative disease. Acta Neuropathol. Commun. 4, 62 (2016). 54. Diao, J. et al. Native a-synuclein induces clustering of synaptic-vesicle mimics via binding to phospholipids and synaptobrevin-2/VAMP2. Elife 2, e00592 (2013). 55. Wang, L. et al. a-synuclein multimers cluster synaptic vesicles and attenuate recycling. Curr. Biol. 24, 2319–2326 (2014). 56. Fioravante, D., Liu, R. Y., Netek, A. K., Cleary, L. J. & Byrne, J. H. Synapsin regulates Basal synaptic strength, synaptic depression, and serotonin-induced facilitation of sensorimotor synapses in Aplysia. J. Neurophysiol. 98, 3568–3580 (2007). 57. Vasileva, M., Renden, R., Horstmann, H., Gitler, D. & Kuner, T. Overexpression of synapsin Ia in the rat calyx of Held accelerates short-term plasticity and decreases synaptic vesicle volume and active zone area. Front. Cell Neurosci. 7, 270 (2013). 58. Zhao, X. et al. Caspase-2 cleavage of tau reversibly impairs memory. Nat. Med. 22, 1268–1276 (2016). 59. Penzes, P. et al. Rapid induction of dendritic spine morphogenesis by transsynaptic ephrinB-EphB receptor activation of the Rho-GEF kalirin. Neuron 37, 263–274 (2003). 60. Rao, A., Cha, E. M. & Craig, A. M. Mismatched appositions of presynaptic and postsynaptic components in isolated hippocampal neurons. J. Neurosci. 20, 8344–8353 (2000). 61. Crimins, J. L. et al. Homeostatic responses by surviving cortical pyramidal cells in neurodegenerative tauopathy. Acta Neuropathol. 122, 551–564 (2011). 62. Decker, J. M. et al. Pro-aggregant Tau impairs mossy fiber plasticity due to structural changes and Ca(þþ) dysregulation. Acta Neuropathol. Commun. 3, 23 (2015). 63. Rocher, A. B. et al. Structural and functional changes in tau mutant mice neurons are not linked to the presence of NFTs. Exp. Neurol. 223, 385–393 (2010). 64. Crone, N. E., Korzeniewska, A. & Franaszczuk, P. J. Cortical g responses: searching high and low. Int. J. Psychophysiol. 79, 9–15 (2011). 65. Herrmann, C. S., Munk, M. H. & Engel, A. K. Cognitive functions of gammaband activity: memory match and utilization. Trends Cogn. Sci. 8, 347–355 (2004). 66. Lachaux, J. P., Axmacher, N., Mormann, F., Halgren, E. & Crone, N. E. Highfrequency neural activity and human cognition: past, present and possible future of intracranial EEG research. Prog Neurobiol. 98, 279–301 (2012). 67. Ferreira, A. & Bigio, E. H. Calpain-mediated tau cleavage: a mechanism leading to neurodegeneration shared by multiple tauopathies. Mol. Med. 17, 676–685 (2011). 68. Vilain, S. et al. Fast and efficient Drosophila melanogaster gene knock-ins using MiMIC transposons. G3 4, 2381–2387 (2014). 69. Uytterhoeven, V., Kuenen, S., Kasprowicz, J., Miskiewicz, K. & Verstreken, P. Loss of skywalker reveals synaptic endosomes as sorting stations for synaptic vesicle proteins. Cell 145, 117–132 (2011). 70. Holt, M., Riedel, D., Stein, A., Schuette, C. & Jahn, R. Synaptic vesicles are constitutively active fusion machines that function independently of Ca2þ. Curr. Biol. 18, 715–722 (2008).-
local.type.refereedRefereed-
local.type.specifiedArticle-
local.bibliographicCitation.artnr15295-
local.classdsPublValOverrule/author_version_not_expected-
dc.identifier.doi10.1038/ncomms15295-
dc.identifier.isi000400962900001-
item.contributorZhou, Lujia-
item.contributorMcInnes, Joseph-
item.contributorWeirda, Keimpe-
item.contributorHolt, Matthew-
item.contributorHerrmann, Abigail G.-
item.contributorJackson, Rosemary J.-
item.contributorWang, Yu-Chun-
item.contributorSwerts, Jef-
item.contributorBeyens, Jelle-
item.contributorMiskiewicz, Katarzyna-
item.contributorVilain, Sven-
item.contributorDEWACHTER, Ilse-
item.contributorMoechars, Diederik-
item.contributorDe Strooper, Bart-
item.contributorSpires-Jones, Tara L.-
item.contributorDe Wit, Joris-
item.contributorVerstreken, Patrik-
item.accessRightsOpen Access-
item.fullcitationZhou, Lujia; McInnes, Joseph; Weirda, Keimpe; Holt, Matthew; Herrmann, Abigail G.; Jackson, Rosemary J.; Wang, Yu-Chun; Swerts, Jef; Beyens, Jelle; Miskiewicz, Katarzyna; Vilain, Sven; DEWACHTER, Ilse; Moechars, Diederik; De Strooper, Bart; Spires-Jones, Tara L.; De Wit, Joris & Verstreken, Patrik (2017) Tau association with synaptic vesicles causes presynaptic dysfunction. In: Nature Communications, 11(8), p. 1-13 (Art N° 15295).-
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item.validationecoom 2018-
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