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Molecular Neurodegeneration
Published in: Molecular Neurodegeneration 1/2017

Open Access 01-12-2017 | Research article

The release and trans-synaptic transmission of Tau via exosomes

Authors: Yipeng Wang, Varun Balaji, Senthilvelrajan Kaniyappan, Lars Krüger, Stephan Irsen, Katharina Tepper, RamReddy Chandupatla, Walter Maetzler, Anja Schneider, Eckhard Mandelkow, Eva-Maria Mandelkow

Published in: Molecular Neurodegeneration | Issue 1/2017

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Abstract

Background

Tau pathology in AD spreads in a hierarchical pattern, whereby it first appears in the entorhinal cortex, then spreads to the hippocampus and later to the surrounding areas. Based on this sequential appearance, AD can be classified into six stages (“Braak stages”). The mechanisms and agents underlying the progression of Tau pathology are a matter of debate. Emerging evidence indicates that the propagation of Tau pathology may be due to the transmission of Tau protein, but the underlying pathways and Tau species are not well understood. In this study we investigated the question of Tau spreading via small extracellular vesicles called exosomes.

Methods

Exosomes from different sources were analyzed by biochemical methods and electron microscopy (EM) and cryo-EM. Microfluidic devices that allow the culture of cell populations in different compartments were used to investigate the spreading of Tau.

Results

We show that Tau protein is released by cultured primary neurons or by N2a cells overexpressing different Tau constructs via exosomes. Neuron-derived exosomal Tau is hypo-phosphorylated, compared with cytosolic Tau. Depolarization of neurons promotes release of Tau-containing exosomes, highlighting the importance of neuronal activity. Using microfluidic devices we show that exosomes mediate trans-neuronal transfer of Tau depending on synaptic connectivity. Tau spreading is achieved by direct transmission of exosomes between neurons. In organotypic hippocampal slices, Tau-containing exosomes in conditioned medium are taken up by neurons and microglia, not astrocytes. In N2a cells, Tau assemblies are released via exosomes. They can induce inclusions of other Tau molecules in N2a cells expressing mutant human Tau. We also studied exosomes from cerebrospinal fluid in AD and control subjects containing monomeric and oligomeric Tau. Split-luciferase complementation reveals that exosomes from CSF can promote Tau aggregation in cultured cells.

Conclusion

Our study demonstrates that exosomes contribute to trans-synaptic Tau transmission, and thus offer new approches to control the spreading of pathology in AD and other tauopathies.
Appendix
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Literature
1.
Mandelkow EM, Mandelkow E. Biochemistry and cell biology of tau protein in neurofibrillary degeneration. Cold Spring Harb Perspect Med. 2012;2:a006247.CrossRefPubMedPubMedCentral
2.
Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82:239–59.CrossRefPubMed
3.
Braak H, Del Tredici K. The pathological process underlying Alzheimer’s disease in individuals under thirty. Acta Neuropathol. 2011;121:171–81.CrossRefPubMed
4.
Braak H, Braak E. Development of Alzheimer-related neurofibrillary changes in the neocortex inversely recapitulates cortical myelogenesis. Acta Neuropathol. 1996;92:197–201.CrossRefPubMed
5.
Yan MH, Wang X, Zhu X. Mitochondrial defects and oxidative stress in Alzheimer disease and Parkinson disease. Free Radic Biol Med. 2013;62:90–101.CrossRefPubMed
6.
Fruhbeis C, Frohlich D, Kuo WP, Amphornrat J, Thilemann S, Saab AS, Kirchhoff F, Mobius W, Goebbels S, Nave KA, et al. Neurotransmitter-triggered transfer of exosomes mediates oligodendrocyte-neuron communication. PLoS Biol. 2013;11:e1001604.CrossRefPubMedPubMedCentral
7.
Hyman BT, Van Hoesen GW, Damasio AR, Barnes CL. Alzheimer’s disease: cell-specific pathology isolates the hippocampal formation. Science. 1984;225:1168–70.CrossRefPubMed
8.
9.
de Calignon A, Polydoro M, Suarez-Calvet M, William C, Adamowicz DH, Kopeikina KJ, Pitstick R, Sahara N, Ashe KH, Carlson GA, et al. Propagation of tau pathology in a model of early Alzheimer’s disease. Neuron. 2012;73:685–97.CrossRefPubMedPubMedCentral
10.
Yamada K, Cirrito JR, Stewart FR, Jiang H, Finn MB, Holmes BB, Binder LI, Mandelkow EM, Diamond MI, Lee VM, Holtzman DM. 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.CrossRefPubMedPubMedCentral
11.
Pooler AM, Phillips EC, Lau DH, Noble W, Hanger DP. Physiological release of endogenous tau is stimulated by neuronal activity. EMBO Rep. 2013;14:389–94.CrossRefPubMedPubMedCentral
12.
Karch CM, Jeng AT, Goate AM. Extracellular Tau levels are influenced by variability in Tau that is associated with tauopathies. J Biol Chem. 2012;287:42751–62.CrossRefPubMedPubMedCentral
13.
Yamada K, Holth JK, Liao F, Stewart FR, Mahan TE, Jiang H, Cirrito JR, Patel TK, Hochgraefe K, Mandelkow E-M, Holtzman DM. Neuronal activity regulates extracellular tau in vivo. J Exp Med. 2014;211:387–93.CrossRefPubMedPubMedCentral
14.
15.
16.
Wu JW, Herman M, Liu L, Simoes S, Acker CM, Figueroa H, Steinberg JI, Margittai M, Kayed R, Zurzolo C, et al. Small misfolded Tau species are internalized via bulk endocytosis and anterogradely and retrogradely transported in neurons. J Biol Chem. 2013;288:1856–70.CrossRefPubMed
17.
Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, Fraser G, Stalder AK, Beibel M, Staufenbiel M, et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol. 2009;11:909–13.CrossRefPubMedPubMedCentral
18.
Mohamed NV, Herrou T, Plouffe V, Piperno N, Leclerc N. Spreading of tau pathology in Alzheimer’s disease by cell-to-cell transmission. Eur J Neurosci. 2013;37:1939–48.CrossRefPubMed
19.
Chivet M, Javalet C, Hemming F, Pernet-Gallay K, Laulagnier K, Fraboulet S, Sadoul R. Exosomes as a novel way of interneuronal communication. Biochem Soc Trans. 2013;41:241–4.CrossRefPubMed
20.
Kowal J, Arras G, Colombo M, Jouve M, Morath JP, Primdal-Bengtson B, Dingli F, Loew D, Tkach M, Thery C. Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. Proc Natl Acad Sci U S A. 2016;113:E968–77.CrossRefPubMedPubMedCentral
21.
Fevrier B, Raposo G. Exosomes: endosomal-derived vesicles shipping extracellular messages. Curr Opin Cell Biol. 2004;16:415–21.CrossRefPubMed
22.
Korkut C, Li Y, Koles K, Brewer C, Ashley J, Yoshihara M, Budnik V. Regulation of postsynaptic retrograde signaling by presynaptic exosome release. Neuron. 2013;77:1039–46.CrossRefPubMedPubMedCentral
23.
Kunadt M, Eckermann K, Stuendl A, Gong J, Russo B, Strauss K, Rai S, Kugler S, Falomir Lockhart L, Schwalbe M, et al. Extracellular vesicle sorting of alpha-Synuclein is regulated by sumoylation. Acta Neuropathol. 2015;129:695–713.CrossRefPubMedPubMedCentral
24.
Rajendran L, Honsho M, Zahn TR, Keller P, Geiger KD, Verkade P, Simons K. Alzheimer’s disease beta-amyloid peptides are released in association with exosomes. Proc Natl Acad Sci U S A. 2006;103:11172–7.CrossRefPubMedPubMedCentral
25.
Fevrier B, Vilette D, Archer F, Loew D, Faigle W, Vidal M, Laude H, Raposo G. Cells release prions in association with exosomes. Proc Natl Acad Sci U S A. 2004;101:9683–8.CrossRefPubMedPubMedCentral
26.
Simon D, Garcia-Garcia E, Gomez-Ramos A, Falcon-Perez JM, Diaz-Hernandez M, Hernandez F, Avila J. Tau overexpression results in its secretion via membrane vesicles. Neurodegener Dis. 2012;10:73–5.CrossRefPubMed
27.
Simon D, Garcia-Garcia E, Royo F, Falcon-Perez JM, Avila J. Proteostasis of tau. Tau overexpression results in its secretion via membrane vesicles. FEBS Lett. 2012;586:47–54.CrossRefPubMed
28.
Saman S, Kim W, Raya M, Visnick Y, Miro S, Saman S, Jackson B, McKee AC, Alvarez VE, Lee NC, Hall GF. 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.CrossRefPubMed
29.
Faure J, Lachenal G, Court M, Hirrlinger J, Chatellard-Causse C, Blot B, Grange J, Schoehn G, Goldberg Y, Boyer V, et al. Exosomes are released by cultured cortical neurones. Mol Cell Neurosci. 2006;31:642–8.CrossRefPubMed
30.
Khlistunova I, Biernat J, Wang Y, Pickhardt M, von Bergen M, Gazova Z, Mandelkow E, Mandelkow EM. Inducible expression of Tau repeat domain in cell models of tauopathy: aggregation is toxic to cells but can be reversed by inhibitor drugs. J Biol Chem. 2006;281:1205–14.CrossRefPubMed
31.
Messing L, Decker JM, Joseph M, Mandelkow E, Mandelkow EM. Cascade of tau toxicity in inducible hippocampal brain slices and prevention by aggregation inhibitors. Neurobiol Aging. 2013;34:1343–54.CrossRefPubMed
32.
Thery C, Amigorena S, Raposo G, Clayton A: Isolation and characterization of exosomes from cell culture supernatants and biological fluids. Curr Protoc Cell Biol 2006, Chapter 3:Unit 3 22.
33.
McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology. 1984;34:939–44.CrossRefPubMed
34.
Stuendl A, Kunadt M, Kruse N, Bartels C, Moebius W, Danzer KM, Mollenhauer B, Schneider A. Induction of alpha-synuclein aggregate formation by CSF exosomes from patients with Parkinson’s disease and dementia with Lewy bodies. Brain. 2016;139:481–94.CrossRefPubMed
35.
Mastronarde DN. Automated electron microscope tomography using robust prediction of specimen movements. J Struct Biol. 2005;152:36–51.CrossRefPubMed
36.
Gunkel M, Schoneberg J, Alkhaldi W, Irsen S, Noe F, Kaupp UB, Al-Amoudi A. Higher-order architecture of rhodopsin in intact photoreceptors and its implication for phototransduction kinetics. Structure. 2015;23:628–38.CrossRefPubMed
37.
Mastronarde DN. Dual-axis tomography: an approach with alignment methods that preserve resolution. J Struct Biol. 1997;120:343–52.CrossRefPubMed
38.
Wang YP, Biernat J, Pickhardt M, Mandelkow E, Mandelkow EM. 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. 2007;104:10252–7.CrossRefPubMedPubMedCentral
39.
Lachenal G, Pernet-Gallay K, Chivet M, Hemming FJ, Belly A, Bodon G, Blot B, Haase G, Goldberg Y, Sadoul R. Release of exosomes from differentiated neurons and its regulation by synaptic glutamatergic activity. Mol Cell Neurosci. 2011;46:409–18.CrossRefPubMed
40.
Gamblin TC, Chen F, Zambrano A, Abraha A, Lagalwar S, Guillozet AL, Lu M, Fu Y, Garcia-Sierra F, LaPointe N, et al. Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer’s disease. Proc Natl Acad Sci U S A. 2003;100:10032–7.CrossRefPubMedPubMedCentral
41.
Dujardin S, Begard S, Caillierez R, Lachaud C, Delattre L, Carrier S, Loyens A, Galas MC, Bousset L, Melki R, et al. Ectosomes: a new mechanism for non-exosomal secretion of tau protein. PLoS One. 2014;9:e100760.CrossRefPubMedPubMedCentral
42.
Palanisamy V, Sharma S, Deshpande A, Zhou H, Gimzewski J, Wong DT. Nanostructural and transcriptomic analyses of human saliva derived exosomes. PLoS One. 2010;5:e8577.CrossRefPubMedPubMedCentral
43.
Lee Y, El Andaloussi S, Wood MJ. Exosomes and microvesicles: extracellular vesicles for genetic information transfer and gene therapy. Hum Mol Genet. 2012;21:R125–34.CrossRefPubMed
44.
Dujardin S, Lecolle K, Caillierez R, Begard S, Zommer N, Lachaud C, Carrier S, Dufour N, Auregan G, Winderickx J, et al. Neuron-to-neuron wild-type Tau protein transfer through a trans-synaptic mechanism: relevance to sporadic tauopathies. Acta Neuropathol Commun. 2014;2:14.CrossRefPubMedPubMedCentral
45.
Wang Y, Martinez-Vicente M, Kruger U, Kaushik S, Wong E, Mandelkow EM, Cuervo AM, Mandelkow E. Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing. Hum Mol Genet. 2009;18:4153–70.CrossRefPubMedPubMedCentral
46.
Takamori S, Holt M, Stenius K, Lemke EA, Gronborg M, Riedel D, Urlaub H, Schenck S, Brugger B, Ringler P, et al. Molecular anatomy of a trafficking organelle. Cell. 2006;127:831–46.CrossRefPubMed
47.
Nickel W and Rabouille C. Mechanisms of regulated unconventional protein secretion.Nat Rev Mol Cell Biol. 2009;10(2):148–55.
48.
Kim W, Lee S, Jung C, Ahmed A, Lee G, Hall GF. Interneuronal transfer of human tau between Lamprey central neurons in situ. J Alzheimers Dis. 2010;19:647–64.PubMed
49.
Santa-Maria I, Varghese M, Ksiezak-Reding H, Dzhun A, Wang J, Pasinetti GM. Paired helical filaments from Alzheimer disease brain induce intracellular accumulation of Tau protein in aggresomes. J Biol Chem. 2012;287:20522–33.CrossRefPubMedPubMedCentral
50.
Kanmert D, Cantlon A, Muratore CR, Jin M, O’Malley TT, Lee G, Young-Pearse TL, Selkoe DJ, Walsh DM. C-Terminally Truncated Forms of Tau, But Not Full-Length Tau or Its C-Terminal Fragments, Are Released from Neurons Independently of Cell Death. J Neurosci. 2015;35:10851–65.CrossRefPubMed
51.
Fiandaca MS, Kapogiannis D, Mapstone M, Boxer A, Eitan E, Schwartz JB, Abner EL, Petersen RC, Federoff HJ, Miller BL, Goetzl EJ. Identification of preclinical Alzheimer’s disease by a profile of pathogenic proteins in neurally derived blood exosomes: A case-control study. Alzheimers Dement. 2015;11:600–7. e601.CrossRefPubMed
52.
Lugli G, Cohen AM, Bennett DA, Shah RC, Fields CJ, Hernandez AG, Smalheiser NR. Plasma Exosomal miRNAs in Persons with and without Alzheimer Disease: Altered Expression and Prospects for Biomarkers. PLoS One. 2015;10:e0139233.CrossRefPubMedPubMedCentral
53.
Danzer KM, Kranich LR, Ruf WP, Cagsal-Getkin O, Winslow AR, Zhu L, Vanderburg CR, McLean PJ. Exosomal cell-to-cell transmission of alpha synuclein oligomers. Mol Neurodegener. 2012;7:42.CrossRefPubMedPubMedCentral
54.
Heusermann W, Hean J, Trojer D, Steib E, von Bueren S, Graff-Meyer A, Genoud C, Martin K, Pizzato N, Voshol J, et al. Exosomes surf on filopodia to enter cells at endocytic hot spots, traffic within endosomes, and are targeted to the ER. J Cell Biol. 2016;213:173–84.CrossRefPubMedPubMedCentral
55.
Asai H, Ikezu S, Tsunoda S, Medalla M, Luebke J, Haydar T, Wolozin B, Butovsky O, Kugler S, Ikezu T. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci. 2015;18:1584–93.CrossRefPubMedPubMedCentral
56.
Calafate S, Buist A, Miskiewicz K, Vijayan V, Daneels G, de Strooper B, de Wit J, Verstreken P, Moechars D. Synaptic Contacts Enhance Cell-to-Cell Tau Pathology Propagation. Cell Rep. 2015;11:1176–83.CrossRefPubMed
57.
Takeda S, Wegmann S, Cho H, DeVos SL, Commins C, Roe AD, Nicholls SB, Carlson GA, Pitstick R, Nobuhara CK, 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.CrossRefPubMedPubMedCentral
58.
d'Abramo C, Acker CM, Jimenez HT, Davies P. Tau passive immunotherapy in mutant P301L mice: antibody affinity versus specificity. PLoS One. 2013;8:e62402.CrossRefPubMedPubMedCentral
59.
Castillo-Carranza DL, Sengupta U, Guerrero-Munoz MJ, Lasagna-Reeves CA, Gerson JE, Singh G, Estes DM, Barrett AD, Dineley KT, Jackson GR, Kayed R. Passive immunization with Tau oligomer monoclonal antibody reverses tauopathy phenotypes without affecting hyperphosphorylated neurofibrillary tangles. J Neurosci. 2014;34:4260–72.CrossRefPubMed
60.
Yanamandra K, Kfoury N, Jiang H, Mahan TE, Ma S, Maloney SE, Wozniak DF, Diamond MI, Holtzman DM. Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Neuron. 2013;80:402–14.CrossRefPubMedPubMedCentral
61.
62.
Fitzner D, Schnaars M, van Rossum D, Krishnamoorthy G, Dibaj P, Bakhti M, Regen T, Hanisch UK, Simons M. Selective transfer of exosomes from oligodendrocytes to microglia by macropinocytosis. J Cell Sci. 2011;124:447–58.CrossRefPubMed
Metadata
Title
The release and trans-synaptic transmission of Tau via exosomes
Authors
Yipeng Wang
Varun Balaji
Senthilvelrajan Kaniyappan
Lars Krüger
Stephan Irsen
Katharina Tepper
RamReddy Chandupatla
Walter Maetzler
Anja Schneider
Eckhard Mandelkow
Eva-Maria Mandelkow
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Molecular Neurodegeneration / Issue 1/2017
Electronic ISSN: 1750-1326
DOI
https://doi.org/10.1186/s13024-016-0143-y

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