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.

Details

Title
Tau exacerbates excitotoxic brain damage in an animal model of stroke
Author
Bi, Mian 1 ; Gladbach, Amadeus 1 ; Janet van Eersel 1 ; Ittner, Arne 1 ; Przybyla, Magdalena 1 ; Annika van Hummel 1 ; Chua, Sook Wern 1 ; van der Hoven, Julia 1 ; Lee, Wei S 1 ; Müller, Julius 2   VIAFID ORCID Logo  ; Parmar, Jasneet 3 ; Georg von Jonquieres 3 ; Stefen, Holly 4 ; Guccione, Ernesto 5 ; Fath, Thomas 6 ; Housley, Gary D 3   VIAFID ORCID Logo  ; Klugmann, Matthias 3   VIAFID ORCID Logo  ; Ke, Yazi D 1 ; Ittner, Lars M 7 

 Dementia Research Unit (DRU), School of Medical Sciences, The University of New South Wales, Sydney, NSW, Australia 
 Division of Cancer Genetics and Therapeutics, Laboratory of Chromatin, Epigenetics & Differentiation, Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore; The Jenner Institute, University of Oxford, Oxford, UK 
 Translational Neuroscience Facility and Department of Physiology, School of Medical Sciences, The University of New South Wales, Sydney, NSW, Australia 
 Neuron Culture Core Facility (NCCF), The University of New South Wales, Sydney, NSW, Australia 
 Division of Cancer Genetics and Therapeutics, Laboratory of Chromatin, Epigenetics & Differentiation, Institute of Molecular and Cell Biology, A*STAR (Agency for Science, Technology and Research), Singapore, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore 
 Neuron Culture Core Facility (NCCF), The University of New South Wales, Sydney, NSW, Australia; Neurodegeneration and Repair Unit (NRU), School of Medical Sciences, The University of New South Wales, Sydney, NSW, Australia 
 Dementia Research Unit (DRU), School of Medical Sciences, The University of New South Wales, Sydney, NSW, Australia; Transgenic Animal Unit, Mark Wainwright Analytical Centre, The University of New South Wales, Sydney, NSW, Australia; Neuroscience Research Australia (NeuRA), Sydney, NSW, Australia 
Pages
1-15
Publication year
2017
Publication date
Sep 2017
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
1936520119
Copyright
© 2017. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.