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Depletion of microglia and inhibition of exosome synthesis halt tau propagation

Nature Neuroscience volume 18, pages 15841593 (2015) | Download Citation

Abstract

Accumulation of pathological tau protein is a major hallmark of Alzheimer's disease. Tau protein spreads from the entorhinal cortex to the hippocampal region early in the disease. Microglia, the primary phagocytes in the brain, are positively correlated with tau pathology, but their involvement in tau propagation is unknown. We developed an adeno-associated virus–based model exhibiting rapid tau propagation from the entorhinal cortex to the dentate gyrus in 4 weeks. We found that depleting microglia dramatically suppressed the propagation of tau and reduced excitability in the dentate gyrus in this mouse model. Moreover, we demonstrate that microglia spread tau via exosome secretion, and inhibiting exosome synthesis significantly reduced tau propagation in vitro and in vivo. These data suggest that microglia and exosomes contribute to the progression of tauopathy and that the exosome secretion pathway may be a therapeutic target.

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Acknowledgements

The authors thank M. Ericsson (Electron Microscopy Facility, Harvard Medical School) for electron microscopic imaging services; P. Davies (Albert Einstein College of Medicine) for providing the MC1, CP13 and PHF1 antibodies; R. Kayed (University of Texas Medical Branch) for providing the T22 polyclonal antibody; Plexxikon, Inc. for providing PLX3397 and control chows; and M. Hasselmo and S. Przedborski for critical reading of the manuscript. This work is supported in part by grants from Alzheimer's Association (T.I.), Alzheimer's Art Quilt Initiative (T.I.), Boston University Alzheimer's Disease Center (P30AG013846, T.I.), BrightFocus Foundation (H.A.) and Coins for Alzheimer's Research Trust (T.I.).

Author information

Affiliations

  1. Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Hirohide Asai
    • , Seiko Ikezu
    • , Satoshi Tsunoda
    • , Benjamin Wolozin
    •  & Tsuneya Ikezu
  2. Department of Anatomy and Neurobiology, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Maria Medalla
    • , Jennifer Luebke
    •  & Tarik Haydar
  3. Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Benjamin Wolozin
    •  & Tsuneya Ikezu
  4. Alzheimer's Disease Center, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Benjamin Wolozin
    •  & Tsuneya Ikezu
  5. Department of Neurology, Center of Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Oleg Butovsky
  6. Center of Nanoscale Microscopy and Physiology of the Brain at Department of Neurology, University Medicine Göttingen, Göttingen, Germany.

    • Sebastian Kügler

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Contributions

T.I. and H.A. designed the AAV-GFP/tau injection mouse model and initiated the study. M.M. and J.L. performed field recording electrophysiology and analyses; S.I. and H.A. cultured primary neuronal cells; H.A., S.I. and T.I. purified exosomes for electron microscopy and biochemical analyses; T.H. performed two-photon imaging and laser-scanning confocal microscopy; O.B. generated and provided the Pr2ry12 antibody, performed data analysis and edited the manuscript; B.W. provided tau antibodies, performed data analysis and wrote the manuscript; S.K. generated and provided AAV vectors, performed data analysis and edited the manuscript; and H.A., S.I., J.L., S.T., M.M. and T.I. designed and performed experiments and data analyses and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Tsuneya Ikezu.

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https://doi.org/10.1038/nn.4132

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