Alzheimer’s disease: Ablating single master site abolishes tau hyperphosphorylation

Hyper-phosphorylation of the neuronal tau protein is a hallmark of neurodegenerative tauopathies like Alzheimer’s disease. A central unanswered question is why tau becomes progressively hyper-phosphorylated. Here, we show that tau phosphorylation is governed by interdependence - a mechanistic link between initial site-specific and subsequent multi-site phosphorylation. Systematic assessment of site interdependence identified distinct residues (Threonine-50, -69, -181) as master sites that determine propagation of phosphorylation at multiple epitopes. CRISPR point mutation and expression of human tau in Alzheimer’s mice showed that site interdependence governs physiologic and amyloid-associated multi-site phosphorylation and cognitive deficits, respectively. Combined targeting of master sites and p38α, the most central tau kinase linked to interdependence, synergistically ablated hyper-phosphorylation. In summary, our work delineates how complex tau phosphorylation arises to inform therapeutic and biomarker design for tauopathies. Methods Raw Immunoblot data for Figure 1. Chemiluninescence signals were imaged on a ChemiDoc MP (Biorad) digital system.