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 & 1 others Lars M. Ittner

*Corresponding author for this work

Research output: Contribution to journalArticle

94 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 languageEnglish
Pages (from-to)904-908
Number of pages5
JournalScience
Volume354
Issue number6314
DOIs
Publication statusPublished - 18 Nov 2016
Externally publishedYes

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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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