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Neuronal activity enhances tau propagation and tau pathology in vivo

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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.


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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 and Affiliations



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.

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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).

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