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

doi:10.1038/s41467-017-00618-0

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 journal › Article › peer-review

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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 language	English
Article number	473
Pages (from-to)	1-15
Number of pages	15
Journal	Nature Communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-00618-0
Publication status	Published - 1 Dec 2017
Externally published	Yes

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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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Bi, M., Gladbach, A., van Eersel, J., Ittner, A., Przybyla, M., van Hummel, A., Chua, S. W., van der Hoven, J., Lee, W. S., Müller, J., Parmar, J., von Jonquieres, G., Stefen, H., Guccione, E., Fath, T., Housley, G. D., Klugmann, M., Ke, Y. D., & Ittner, L. M. (2017). Tau exacerbates excitotoxic brain damage in an animal model of stroke. Nature Communications, 8(1), 1-15. [473]. https://doi.org/10.1038/s41467-017-00618-0

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title = "Tau exacerbates excitotoxic brain damage in an animal model of stroke",

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.",

author = "Mian Bi and Amadeus Gladbach and {van Eersel}, Janet and Arne Ittner and Magdalena Przybyla and {van Hummel}, Annika and Chua, {Sook Wern} and {van der Hoven}, Julia and Lee, {Wei S.} and Julius M{\"u}ller and Jasneet Parmar and {von Jonquieres}, Georg and Holly Stefen and Ernesto Guccione and Thomas Fath and Housley, {Gary D.} and Matthias Klugmann and Ke, {Yazi D.} and Ittner, {Lars M.}",

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.",

year = "2017",

month = dec,

day = "1",

doi = "10.1038/s41467-017-00618-0",

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Bi, M, Gladbach, A, van Eersel, J, Ittner, A, Przybyla, M , van Hummel, A, Chua, SW, van der Hoven, J, Lee, WS, Müller, J, Parmar, J, von Jonquieres, G, Stefen, H, Guccione, E, Fath, T, Housley, GD, Klugmann, M, Ke, YD & Ittner, LM 2017, 'Tau exacerbates excitotoxic brain damage in an animal model of stroke', Nature Communications, vol. 8, no. 1, 473, pp. 1-15. https://doi.org/10.1038/s41467-017-00618-0

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T1 - Tau exacerbates excitotoxic brain damage in an animal model of stroke

AU - Bi, Mian

AU - Gladbach, Amadeus

AU - van Eersel, Janet

AU - Ittner, Arne

AU - Przybyla, Magdalena

AU - van Hummel, Annika

AU - Chua, Sook Wern

AU - van der Hoven, Julia

AU - Lee, Wei S.

AU - Müller, Julius

AU - Parmar, Jasneet

AU - von Jonquieres, Georg

AU - Stefen, Holly

AU - Guccione, Ernesto

AU - Fath, Thomas

AU - Housley, Gary D.

AU - Klugmann, Matthias

AU - Ke, Yazi D.

AU - Ittner, Lars M.

N1 - 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.

PY - 2017/12/1

Y1 - 2017/12/1

N2 - 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.

AB - 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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VL - 8

SP - 1

EP - 15

JO - Nature Communications

JF - Nature Communications

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ER -

Tau exacerbates excitotoxic brain damage in an animal model of stroke

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