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

 

Ittner, A., Chua SW., Bertz, J. et al.

Science 2016, vol:354(6314), 904-908 doi: 10.1126/science.aah6205

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.

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Topics: Neurodegenerative diseases, Monolith – MicroScale Thermophoresis, MST,  Publications

 

 

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