Site-specific phosphorylation of tau inhibits amyloid-β toxicity in Alzheimer's mice

Arne Ittner; Sook Wern Chua; Josefine Bertz; Alexander Volkerling; Julia van der Hoven; Amadeus Gladbach; Magdalena Przybyla; Mian Bi; Annika van Hummel; Claire H. Stevens; Stefania Ippati; Lisa S. Suh; Alexander Macmillan; Greg Sutherland; Jillian J. Kril; Ana P. G. Silva; Joel Mackay; Anne Poljak; Fabien Delerue; Yazi D. Ke; Lars M. Ittner

doi:10.1126/science.aah6205

Site-specific phosphorylation of tau inhibits amyloid-β toxicity in Alzheimer's mice

Arne Ittner^*, Sook Wern Chua, Josefine Bertz, Alexander Volkerling, Julia van der Hoven, Amadeus Gladbach, Magdalena Przybyla, Mian Bi, Annika van Hummel, Claire H. Stevens, Stefania Ippati, Lisa S. Suh, Alexander Macmillan, Greg Sutherland, Jillian J. Kril, Ana P. G. Silva, Joel Mackay, Anne Poljak, Fabien Delerue, Yazi D. KeLars M. Ittner

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

213 Citations (Scopus)

Abstract

Amyloid-β (Aβ) toxicity in Alzheimer's disease (AD) is considered to be mediated by phosphorylated tau protein. In contrast, we found that, at least in early disease, site-specific phosphorylation of tau inhibited Aβ toxicity. This specific tau phosphorylation was mediated by the neuronal p38 mitogen-activated protein kinase p38γ and interfered with postsynaptic excitotoxic signaling complexes engaged by Aβ. Accordingly, depletion of p38γ exacerbated neuronal circuit aberrations, cognitive deficits, and premature lethality in a mousemodel of AD, whereas increasing the activity of p38γ abolished these deficits. Furthermore, mimicking site-specific tau phosphorylation alleviated Aβ-induced neuronal death and offered protection from excitotoxicity. Our work provides insights into postsynaptic processes in AD pathogenesis and challenges a purely pathogenic role of tau phosphorylation in neuronal toxicity.

Original language	English
Pages (from-to)	904-908
Number of pages	5
Journal	Science
Volume	354
Issue number	6314
DOIs	https://doi.org/10.1126/science.aah6205 https://doi.org/10.1126/science.aam9523
Publication status	Published - 18 Nov 2016
Externally published	Yes

Bibliographical note

A correction exists for this article and can be found in Science (2017) Vol. 355(6326) at doi: 10.1126/science.aam9523

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Ittner, A., Chua, S. W., Bertz, J., Volkerling, A., van der Hoven, J., Gladbach, A., Przybyla, M., Bi, M., van Hummel, A., Stevens, C. H., Ippati, S., Suh, L. S., Macmillan, A., Sutherland, G., Kril, J. J., Silva, A. P. G., Mackay, J., Poljak, A., Delerue, F., ... Ittner, L. M. (2016). Site-specific phosphorylation of tau inhibits amyloid-β toxicity in Alzheimer's mice. Science, 354(6314), 904-908. https://doi.org/10.1126/science.aah6205, https://doi.org/10.1126/science.aam9523

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title = "Site-specific phosphorylation of tau inhibits amyloid-β toxicity in Alzheimer's mice",

abstract = "Amyloid-β (Aβ) toxicity in Alzheimer's disease (AD) is considered to be mediated by phosphorylated tau protein. In contrast, we found that, at least in early disease, site-specific phosphorylation of tau inhibited Aβ toxicity. This specific tau phosphorylation was mediated by the neuronal p38 mitogen-activated protein kinase p38γ and interfered with postsynaptic excitotoxic signaling complexes engaged by Aβ. Accordingly, depletion of p38γ exacerbated neuronal circuit aberrations, cognitive deficits, and premature lethality in a mousemodel of AD, whereas increasing the activity of p38γ abolished these deficits. Furthermore, mimicking site-specific tau phosphorylation alleviated Aβ-induced neuronal death and offered protection from excitotoxicity. Our work provides insights into postsynaptic processes in AD pathogenesis and challenges a purely pathogenic role of tau phosphorylation in neuronal toxicity.",

author = "Arne Ittner and Chua, {Sook Wern} and Josefine Bertz and Alexander Volkerling and {van der Hoven}, Julia and Amadeus Gladbach and Magdalena Przybyla and Mian Bi and {van Hummel}, Annika and Stevens, {Claire H.} and Stefania Ippati and Suh, {Lisa S.} and Alexander Macmillan and Greg Sutherland and Kril, {Jillian J.} and Silva, {Ana P. G.} and Joel Mackay and Anne Poljak and Fabien Delerue and Ke, {Yazi D.} and Ittner, {Lars M.}",

note = "A correction exists for this article and can be found in Science (2017) Vol. 355(6326) at doi: 10.1126/science.aam9523",

year = "2016",

month = nov,

day = "18",

doi = "10.1126/science.aah6205",

language = "English",

volume = "354",

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Ittner, A, Chua, SW, Bertz, J, Volkerling, A, van der Hoven, J, Gladbach, A, Przybyla, M, Bi, M, van Hummel, A, Stevens, CH, Ippati, S, Suh, LS, Macmillan, A, Sutherland, G, Kril, JJ, Silva, APG, Mackay, J, Poljak, A, Delerue, F , Ke, YD & Ittner, LM 2016, 'Site-specific phosphorylation of tau inhibits amyloid-β toxicity in Alzheimer's mice', Science, vol. 354, no. 6314, pp. 904-908. https://doi.org/10.1126/science.aah6205, https://doi.org/10.1126/science.aam9523

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T1 - Site-specific phosphorylation of tau inhibits amyloid-β toxicity in Alzheimer's mice

AU - Ittner, Arne

AU - Chua, Sook Wern

AU - Bertz, Josefine

AU - Volkerling, Alexander

AU - van der Hoven, Julia

AU - Gladbach, Amadeus

AU - Przybyla, Magdalena

AU - Bi, Mian

AU - van Hummel, Annika

AU - Stevens, Claire H.

AU - Ippati, Stefania

AU - Suh, Lisa S.

AU - Macmillan, Alexander

AU - Sutherland, Greg

AU - Kril, Jillian J.

AU - Silva, Ana P. G.

AU - Mackay, Joel

AU - Poljak, Anne

AU - Delerue, Fabien

AU - Ke, Yazi D.

AU - Ittner, Lars M.

N1 - A correction exists for this article and can be found in Science (2017) Vol. 355(6326) at doi: 10.1126/science.aam9523

PY - 2016/11/18

Y1 - 2016/11/18

N2 - Amyloid-β (Aβ) toxicity in Alzheimer's disease (AD) is considered to be mediated by phosphorylated tau protein. In contrast, we found that, at least in early disease, site-specific phosphorylation of tau inhibited Aβ toxicity. This specific tau phosphorylation was mediated by the neuronal p38 mitogen-activated protein kinase p38γ and interfered with postsynaptic excitotoxic signaling complexes engaged by Aβ. Accordingly, depletion of p38γ exacerbated neuronal circuit aberrations, cognitive deficits, and premature lethality in a mousemodel of AD, whereas increasing the activity of p38γ abolished these deficits. Furthermore, mimicking site-specific tau phosphorylation alleviated Aβ-induced neuronal death and offered protection from excitotoxicity. Our work provides insights into postsynaptic processes in AD pathogenesis and challenges a purely pathogenic role of tau phosphorylation in neuronal toxicity.

AB - Amyloid-β (Aβ) toxicity in Alzheimer's disease (AD) is considered to be mediated by phosphorylated tau protein. In contrast, we found that, at least in early disease, site-specific phosphorylation of tau inhibited Aβ toxicity. This specific tau phosphorylation was mediated by the neuronal p38 mitogen-activated protein kinase p38γ and interfered with postsynaptic excitotoxic signaling complexes engaged by Aβ. Accordingly, depletion of p38γ exacerbated neuronal circuit aberrations, cognitive deficits, and premature lethality in a mousemodel of AD, whereas increasing the activity of p38γ abolished these deficits. Furthermore, mimicking site-specific tau phosphorylation alleviated Aβ-induced neuronal death and offered protection from excitotoxicity. Our work provides insights into postsynaptic processes in AD pathogenesis and challenges a purely pathogenic role of tau phosphorylation in neuronal toxicity.

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VL - 354

SP - 904

EP - 908

JO - Science

JF - Science

IS - 6314

ER -

Site-specific phosphorylation of tau inhibits amyloid-β toxicity in Alzheimer's mice

Abstract

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