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 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.

Identification of the Tau phosphorylation pattern that drives its aggregation

“…2 and 4) suggests the initial turn-like structure induced by the phosphorylation of only Ser202 and Thr205 is protective against aggregation. A protective role for the phosphorylation of Tau at the Thr205 position was equally proposed for the synaptic pool of Tau, not in the aggregation process but, rather, in the attenuation of the Aβ oligomerinduced toxicity (42). Importantly, here, our resulting fibers show several characteristics of the natural fibers that fill the neurons of patients with AD, such as robust AT8 staining (Fig.…”

An N-terminal motif unique to primate tau enables differential protein–protein interactions

“…Protein-protein interactions of tau have been shown to be critical for the role of tau in Aβ toxicity in Alzheimer's disease (AD) (8). Furthermore, interactions of tau with other factors that mediate intracellular signals can be modulated through post-translational modifications on tau or intrinsic factors in tau (7,15,20,21). The Nterminal region of human tau is defined by splicing-dependent inclusions of 2 primary sequence segments, that contribute to differential functions of tau regarding protein interactions or localization (20).…”

“…In addition, tau protein interactions are dynamically regulated, likely reflecting changes in neuronal states of excitation/inhibition or other cellular processes. Post-translational modification of tau, such as phosphorylation, can affect tau complex formation with resulting changes in tau downstream signalling, imparting tau with detrimental (13,14), but also beneficial (15) properties in relation to Aβ toxicity. Finally, in familial forms of tauopathies (=neurological diseases with tau pathology), tau mutations affect protein interactions with tau (16).…”

Alzheimer’s disease as an inflammatory disease

“…In this way, tau toxicity could result in an inflammatory process that could be prevented by the inhibition of tau kinases, like GSK3 (77). However, tau phosphorylation at different residues could result in different toxicity levels and even a site-specific phosphorylation of tau could inhibit amyloid toxicity, in a mouse model (78).…”