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Tau exacerbates excitotoxic brain damage in an animal model of stroke

Author

Listed:
  • Mian Bi

    (The University of New South Wales)

  • Amadeus Gladbach

    (The University of New South Wales)

  • Janet Eersel

    (The University of New South Wales)

  • Arne Ittner

    (The University of New South Wales)

  • Magdalena Przybyla

    (The University of New South Wales)

  • Annika Hummel

    (The University of New South Wales)

  • Sook Wern Chua

    (The University of New South Wales)

  • Julia van der Hoven

    (The University of New South Wales)

  • Wei S. Lee

    (The University of New South Wales)

  • Julius Müller

    (A*STAR (Agency for Science, Technology and Research)
    University of Oxford)

  • Jasneet Parmar

    (The University of New South Wales)

  • Georg von Jonquieres

    (The University of New South Wales)

  • Holly Stefen

    (The University of New South Wales)

  • Ernesto Guccione

    (A*STAR (Agency for Science, Technology and Research)
    National University of Singapore)

  • Thomas Fath

    (The University of New South Wales
    The University of New South Wales)

  • Gary D. Housley

    (The University of New South Wales)

  • Matthias Klugmann

    (The University of New South Wales)

  • Yazi D. Ke

    (The University of New South Wales)

  • Lars M. Ittner

    (The University of New South Wales
    The University of New South Wales
    Neuroscience Research Australia (NeuRA))

Abstract

Neuronal excitotoxicity induced by aberrant excitation of glutamatergic receptors contributes to brain damage in stroke. Here we show that tau-deficient (tau−/−) mice are profoundly protected from excitotoxic brain damage and neurological deficits following experimental stroke, using a middle cerebral artery occlusion with reperfusion model. Mechanistically, we show that this protection is due to site-specific inhibition of glutamate-induced and Ras/ERK-mediated toxicity by accumulation of Ras-inhibiting SynGAP1, which resides in a post-synaptic complex with tau. Accordingly, reducing SynGAP1 levels in tau−/− mice abolished the protection from pharmacologically induced excitotoxicity and middle cerebral artery occlusion-induced brain damage. Conversely, over-expression of SynGAP1 prevented excitotoxic ERK activation in wild-type neurons. Our findings suggest that tau mediates excitotoxic Ras/ERK signaling by controlling post-synaptic compartmentalization of SynGAP1.

Suggested Citation

  • Mian Bi & Amadeus Gladbach & Janet Eersel & Arne Ittner & Magdalena Przybyla & Annika Hummel & Sook Wern Chua & Julia van der Hoven & Wei S. Lee & Julius Müller & Jasneet Parmar & Georg von Jonquieres, 2017. "Tau exacerbates excitotoxic brain damage in an animal model of stroke," Nature Communications, Nature, vol. 8(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00618-0
    DOI: 10.1038/s41467-017-00618-0
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    Cited by:

    1. Rebecca San Gil & Dana Pascovici & Juliana Venturato & Heledd Brown-Wright & Prachi Mehta & Lidia Madrid San Martin & Jemma Wu & Wei Luan & Yi Kit Chui & Adekunle T. Bademosi & Shilpa Swaminathan & Se, 2024. "A transient protein folding response targets aggregation in the early phase of TDP-43-mediated neurodegeneration," Nature Communications, Nature, vol. 15(1), pages 1-23, December.

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