Tau exacerbates excitotoxic brain damage in an animal model of stroke

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, Holly Stefen, Ernesto Guccione, Thomas Fath, Gary D. Housley, Matthias Klugmann, Yazi D. Ke and Lars M. Ittner ()
Additional contact information
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)
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)
Thomas Fath: 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

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00618-0

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