Tau exacerbates excitotoxic brain damage in an animal model of stroke

Mian Bi, Amadeus Gladbach, Janet van Eersel, Arne Ittner, Magdalena Przybyla, Annika van 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, Lars M. Ittner*

*Corresponding author for this work

Research output: Contribution to journalArticle

41 Citations (Scopus)
18 Downloads (Pure)

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.

Original languageEnglish
Article number473
Pages (from-to)1-15
Number of pages15
JournalNature Communications
Volume8
Issue number1
DOIs
Publication statusPublished - 1 Dec 2017
Externally publishedYes

Bibliographical note

Copyright the Author(s) 2017. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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