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Neuronal activity enhances tau propagation and tau pathology in vivo

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Abstract

Tau protein can transfer between neurons transneuronally and trans-synaptically, which is thought to explain the progressive spread of tauopathy observed in the brain of patients with Alzheimer's disease. Here we show that physiological tau released from donor cells can transfer to recipient cells via the medium, suggesting that at least one mechanism by which tau can transfer is via the extracellular space. Neuronal activity has been shown to regulate tau secretion, but its effect on tau pathology is unknown. Using optogenetic and chemogenetic approaches, we found that increased neuronal activity stimulates the release of tau in vitro and enhances tau pathology in vivo. These data have implications for disease pathogenesis and therapeutic strategies for Alzheimer's disease and other tauopathies.

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Figure 1: Endogenously generated hTau can transfer from cell to cell.
Figure 2: Endogenously generated hTau aggregates can transfer from cell to cell.
Figure 3: Seed-induced tau pathology propagates from cell to cell.
Figure 4: Tau from mouse primary neurons and human iPSCs can transfer via the extracellular medium.
Figure 5: Tau release is enhanced by stimulating neuronal activity.
Figure 6: Transfer of tau from cell to cell is enhanced by stimulating neuronal activity.
Figure 7: Optogenetically induced increased neuronal activity exacerbates tau pathology in the hippocampus.
Figure 8: Chemogenetically induced increased neuronal activity accelerates tau pathology in the EC.

Change history

  • 08 July 2016

    In the version of this article initially published online, the second author's name was given as Syed A Hussaini; it should have read S Abid Hussaini. In the legend to Figure 8b, "left EC" and "right EC" were reversed. In the Author Contributions, Y.H.F. was listed among those performing mouse surgery, in vivo recordings, in vivo stimulations and immunohistochemistry; it should have been H.F. And in the Online Methods section on statistical analyses and sample sizes, it was stated that statistical significance was determined if the adjusted P was 0.05; this should have read <0.05. Finally, scale bars were missing for Supplementary Figures 2 and 3. The errors have been corrected for the print, PDF and HTML versions of this article.

References

  1. Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239–259 (1991).

    CAS  PubMed  Google Scholar 

  2. Liu, L. et al. Trans-synaptic spread of tau pathology in vivo. PLoS One 7, e31302 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. de Calignon, A. et al. Propagation of tau pathology in a model of early Alzheimer's disease. Neuron 73, 685–697 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Harris, J.A. et al. Human P301L-mutant tau expression in mouse entorhinal-hippocampal network causes tau aggregation and presynaptic pathology but no cognitive deficits. PLoS One 7, e45881 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Clavaguera, F. et al. Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc. Natl. Acad. Sci. USA 110, 9535–9540 (2013).

    CAS  PubMed  Google Scholar 

  6. Clavaguera, F. et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat. Cell Biol. 11, 909–913 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Iba, M. et al. Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer's-like tauopathy. J. Neurosci. 33, 1024–1037 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Sanders, D.W. et al. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 82, 1271–1288 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Wu, J.W. et al. Small misfolded Tau species are internalized via bulk endocytosis and anterogradely and retrogradely transported in neurons. J. Biol. Chem. 288, 1856–1870 (2013).

    CAS  PubMed  Google Scholar 

  10. 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. 21, 1358–1368 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Osinde, M., Clavaguera, F., May-Nass, R., Tolnay, M. & Dev, K.K. Lentivirus Tau (P301S) expression in adult amyloid precursor protein (APP)-transgenic mice leads to tangle formation. Neuropathol. Appl. Neurobiol. 34, 523–531 (2008).

    CAS  PubMed  Google Scholar 

  12. Kfoury, N., Holmes, B.B., Jiang, H., Holtzman, D.M. & Diamond, M.I. Trans-cellular propagation of Tau aggregation by fibrillar species. J. Biol. Chem. 287, 19440–19451 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Gousset, K. et al. Prions hijack tunnelling nanotubes for intercellular spread. Nat. Cell Biol. 11, 328–336 (2009).

    CAS  PubMed  Google Scholar 

  14. 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. 287, 3842–3849 (2012).

    CAS  PubMed  Google Scholar 

  15. Asai, H. et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat. Neurosci. 18, 1584–1593 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Simón, D. et al. Tau overexpression results in its secretion via membrane vesicles. Neurodegener. Dis. 10, 73–75 (2012).

    PubMed  Google Scholar 

  17. Dujardin, S. et al. Ectosomes: a new mechanism for non-exosomal secretion of tau protein. PLoS One 9, e100760 (2014).

    PubMed  PubMed Central  Google Scholar 

  18. 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. 31, 13110–13117 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Barten, D.M. et al. Tau transgenic mice as models for cerebrospinal fluid tau biomarkers. J. Alzheimers Dis. 24 (suppl.) 2: 127–141 (2011).

    CAS  PubMed  Google Scholar 

  20. Takeda, S. et al. Neuronal uptake and propagation of a rare phosphorylated high-molecular-weight tau derived from Alzheimer's disease brain. Nat. Commun. 6, 8490 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Kurz, A. et al. Tau protein in cerebrospinal fluid is significantly increased at the earliest clinical stage of Alzheimer disease. Alzheimer Dis. Assoc. Disord. 12, 372–377 (1998).

    CAS  PubMed  Google Scholar 

  22. Pooler, A.M., Phillips, E.C., Lau, D.H., Noble, W. & Hanger, D.P. Physiological release of endogenous tau is stimulated by neuronal activity. EMBO Rep. 14, 389–394 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Yamada, K. et al. Neuronal activity regulates extracellular tau in vivo. J. Exp. Med. 211, 387–393 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Busche, M.A. et al. Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer's disease. Science 321, 1686–1689 (2008).

    CAS  PubMed  Google Scholar 

  25. Busche, M.A. et al. Critical role of soluble amyloid-β for early hippocampal hyperactivity in a mouse model of Alzheimer's disease. Proc. Natl. Acad. Sci. USA 109, 8740–8745 (2012).

    CAS  PubMed  Google Scholar 

  26. Šišková, Z. et al. Dendritic structural degeneration is functionally linked to cellular hyperexcitability in a mouse model of Alzheimer's disease. Neuron 84, 1023–1033 (2014).

    PubMed  Google Scholar 

  27. Minkeviciene, R. et al. Amyloid beta-induced neuronal hyperexcitability triggers progressive epilepsy. J. Neurosci. 29, 3453–3462 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Hall, A.M. et al. Tau-dependent Kv4.2 depletion and dendritic hyperexcitability in a mouse model of Alzheimer's disease. J. Neurosci. 35, 6221–6230 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Santacruz, K. et al. Tau suppression in a neurodegenerative mouse model improves memory function. Science 309, 476–481 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Tucker, K.L., Meyer, M. & Barde, Y.A. Neurotrophins are required for nerve growth during development. Nat. Neurosci. 4, 29–37 (2001).

    CAS  PubMed  Google Scholar 

  31. Taylor, A.M. et al. A microfluidic culture platform for CNS axonal injury, regeneration and transport. Nat. Methods 2, 599–605 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Styren, S.D., Hamilton, R.L., Styren, G.C. & Klunk, W.E. X-34, a fluorescent derivative of Congo red: a novel histochemical stain for Alzheimer's disease pathology. J. Histochem. Cytochem. 48, 1223–1232 (2000).

    CAS  PubMed  Google Scholar 

  33. Shi, Y., Kirwan, P. & Livesey, F.J. Directed differentiation of human pluripotent stem cells to cerebral cortex neurons and neural networks. Nat. Protoc. 7, 1836–1846 (2012).

    CAS  PubMed  Google Scholar 

  34. Shi, Y., Kirwan, P., Smith, J., Robinson, H.P. & Livesey, F.J. Human cerebral cortex development from pluripotent stem cells to functional excitatory synapses. Nat. Neurosci. 15, 477–486 (2012).

    CAS  PubMed  Google Scholar 

  35. Sposito, T. et al. Developmental regulation of tau splicing is disrupted in stem cell-derived neurons from frontotemporal dementia patients with the 10 + 16 splice-site mutation in MAPT. Hum. Mol. Genet. 24, 5260–5269 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Yoon, K.W., Covey, D.F. & Rothman, S.M. Multiple mechanisms of picrotoxin block of GABA-induced currents in rat hippocampal neurons. J. Physiol. (Lond.) 464, 423–439 (1993).

    CAS  Google Scholar 

  37. Boyden, E.S., Zhang, F., Bamberg, E., Nagel, G. & Deisseroth, K. Millisecond-timescale, genetically targeted optical control of neural activity. Nat. Neurosci. 8, 1263–1268 (2005).

    CAS  PubMed  Google Scholar 

  38. Zhu, H. & Roth, B.L. DREADD: a chemogenetic GPCR signaling platform. Int. J. Neuropsychopharmacol. 18, pyu007 (2015).

    Google Scholar 

  39. Frost, B., Jacks, R.L. & Diamond, M.I. Propagation of tau misfolding from the outside to the inside of a cell. J. Biol. Chem. 284, 12845–12852 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Guo, J.L. & Lee, V.M. Seeding of normal Tau by pathological Tau conformers drives pathogenesis of Alzheimer-like tangles. J. Biol. Chem. 286, 15317–15331 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Michel, C.H. et al. Extracellular monomeric tau protein is sufficient to initiate the spread of tau protein pathology. J. Biol. Chem. 289, 956–967 (2014).

    CAS  PubMed  Google Scholar 

  42. Yamada, K. et al. Analysis of in vivo turnover of tau in a mouse model of tauopathy. Mol. Neurodegener. 10, 55 (2015).

    PubMed  PubMed Central  Google Scholar 

  43. Holmes, B.B. et al. Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds. Proc. Natl. Acad. Sci. USA 110, E3138–E3147 (2013).

    CAS  PubMed  Google Scholar 

  44. Mirbaha, H., Holmes, B.B., Sanders, D.W., Bieschke, J. & Diamond, M.I. Tau trimers are the minimal propagation unit spontaneously internalized to seed intracellular aggregation. J. Biol. Chem. 290, 14893–14903 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Santa-Maria, I. et al. Paired helical filaments from Alzheimer disease brain induce intracellular accumulation of Tau protein in aggresomes. J. Biol. Chem. 287, 20522–20533 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Bomben, V. et al. Bexarotene reduces network excitability in models of Alzheimer's disease and epilepsy. Neurobiol. Aging 35, 2091–2095 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Sanchez, P.E. et al. Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer's disease model. Proc. Natl. Acad. Sci. USA 109, E2895–E2903 (2012).

    CAS  PubMed  Google Scholar 

  48. Busche, M.A. et al. Rescue of long-range circuit dysfunction in Alzheimer's disease models. Nat. Neurosci. 18, 1623–1630 (2015).

    CAS  PubMed  Google Scholar 

  49. Thom, M. et al. Neurofibrillary tangle pathology and Braak staging in chronic epilepsy in relation to traumatic brain injury and hippocampal sclerosis: a post-mortem study. Brain 134, 2969–2981 (2011).

    PubMed  PubMed Central  Google Scholar 

  50. Acker, C.M., Forest, S.K., Zinkowski, R., Davies, P. & d'Abramo, C. Sensitive quantitative assays for tau and phospho-tau in transgenic mouse models. Neurobiol. Aging 34, 338–350 (2013).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank C. Acker for help with Sandwich ELISA and P. Davies (Litwin Zucker Center for Alzheimer's Research, Feinstein Institute, New York, USA) for providing tau antibodies. We thank K. Jansen-West, E. Perkerson and L. Petrucelli (Mayo Clinic Jacksonville) for providing additional tau viruses and D. Sulzer for discussions regarding cell electrophysiology. We also thank L. Liu for assistance with mouse tissue collection, C. Profaci for assistance with optogenetic experiments and L. Shi for administrative assistance. This work was supported by a BrightFocus Foundation fellowship to J.W., NIH/NINDS grants NS081555 and NS074874 to K.E.D., Cure Alzheimer's Fund to K.E.D., the Parkinson's Disease Foundation to D.S and NIH/NIA grant AG050425 to S.A.H. and K.E.D. A.M. is supported by funds from NIH/NIA AA19801. S.W. is supported by the NIHR Queen Square Dementia Biomedical Research Unit.

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Authors

Contributions

J.W.W. and K.E.D. designed the experiments. J.W.W., S.A.H., I.M.B., A.M. and S.W. conducted the experiments and data analyses. J.W.W., C.L.C. and K.E.D. wrote the manuscript. M.H., E.N., S.E. and Y.H.F. provided technical assistance. S.A.H., I.M.B., G.A.R. and H.F. performed mouse surgery, in vivo recordings, in vivo stimulations and immunohistochemistry. A.M. performed in vitro patch-clamp experiments, and, providing the LED microscope, optimization of in vitro optogenetic stimulation. K.R. and C.L.C. performed the qRT-PCR experiment and, together with C.C., performed AAV P301L-GFP, GFP and WT-GFP virus cloning, packaging and titration. C.L.C. performed statistical analyses. D.W.S. and M.I.D. provided cell lysates containing tau seeds and repeat-domain PSY, YFP and mCherry viruses. I.M.B. performed Nissl and immunofluorescence analysis. S.W. performed iPSC differentiation and data analysis and provided conditioned media. R.A.C.M.B. performed immunoprecipitation of tau from conditioned media and cell lysates.

Corresponding author

Correspondence to Karen E Duff.

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Integrated supplementary information

Supplementary Figure 1 Increased neuronal activity does not change human tau expression in the stimulated mice.

To adjust for total neuron count, the expression ratio of hTau/NeuN was plotted for animals 1- 6 (line rTg4510, N = 6). There was no significant difference between stimulated (mean ratio = 1.92 ± 1.28) versus non-stimulated (mean ratio = 2.43 ± 1.54) hemispheres; t(5) = -1.57, P = 0.18.

Supplementary Figure 2 Immunohistochemistry image of brain tissue of EC-tau mice stimulated for 2 weeks.

Anti–human tau antibody MC1 (green), DAPI (blue). Scale bar, 500 μm. N = 1 mouse.

Supplementary Figure 3 Immunohistochemistry image of brain tissue of EC-tau mice stimulated for 6 weeks.

Brain tissues were stained with (a) anti-human tau antibody, MC1 (green) acquired using lower green laser power, or (b) CP27. DAPI (blue). Scale bar, 500 μm. N = 3 mice.

Supplementary Figure 4 Full-length images of western blots presented in Figure 4a.

Lysate from tau-expressing neurons (rTg4510 primary neurons and P301L-GFP transduced neurons) and conditioned media from the same cells was immunoprecipitated with anti-hTau antibody (CP27) and analyzed by immunoblot with total tau antibody (TauC). Actin shows amounts of protein loaded and absence of cell contamination in conditioned media.

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Wu, J., Hussaini, S., Bastille, I. et al. Neuronal activity enhances tau propagation and tau pathology in vivo. Nat Neurosci 19, 1085–1092 (2016). https://doi.org/10.1038/nn.4328

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