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

Authors

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

RIS ID

111310

Publication Details

Ittner, A., Chua, S., 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., Silva, A. P. G., Mackay, J., Poljak, A., Delerue, F., Ke, Y. D. & Ittner, L. M. (2016). Site-specific phosphorylation of tau inhibits amyloid-β toxicity in Alzheimer’s mice. Science, 354 (6314), 904-908.

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 mouse model 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.