Bi, M., Gladbach, A., van Eersel, J., Ittner, A., Przybyla, M., van Hummel, A., … Ittner, L. M. (2017). Tau exacerbates excitotoxic brain damage in an animal model of stroke. Nature Communications, 8(1). doi:10.1038/s41467-017-00618-0
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.
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The authors thank Dr Vladimir Sytnyk for help with confocal microscopy, the staff of the Biological Resources Center Wallace Wurth animal facility for continuing support with mice, Dr Peter Davies for antibodies, and Dr David W Howells, Dr Geoffrey A Donnan (both: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Australia), Dr Edna Hardeman (University of New South Wales, Australia) and Dr Nikolas Haass (University of Queensland, Australia) for helpful comments on the manuscript. This work was supported by funding from the National Health and Medical Research Council (NH&MRC), the Australian Research Council (ARC), the Alzheimer Association (US), Alzheimer’s Australia, the Jane Mason & Harold Stannett Williams Memorial Foundation (Australia) and the University of New South Wales. L.M.I. is an NH&MRC Senior Research Fellow. Y.D.K. is an NH&MRC Career Development Fellow. J.v.E. is an ARC DECRA fellow.This research is supported by core funding from IMCB/A*STAR