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

Amyloid-b (A beta) 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 A beta toxicity. This specific tau phosphorylation was mediated by the neuronal p38 mitogen-activated protein kinase p38 gamma and interfered with postsynaptic excitotoxic signaling complexes engaged by A beta. Accordingly, depletion of p38 gamma exacerbated neuronal circuit aberrations, cognitive deficits, and premature lethality in a mousemodel of AD, whereas increasing the activity of p38 gamma abolished these deficits. Furthermore, mimicking site-specific tau phosphorylation alleviated A beta-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.