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

Kristie Stefanoska, Mehul Gajwani, Amanda R.P. Tan, Holly I. Ahel, Prita R. Asih, Alexander Volkerling, Anne Poljak, Arne Ittner

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Abstract

Hyperphosphorylation of the neuronal tau protein is a hallmark of neurodegenerative tauopathies such as Alzheimer's disease. A central unanswered question is why tau becomes progressively hyperphosphorylated. 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, threonine-69, and threonine-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 hyperphosphorylation. In summary, our work delineates how complex tau phosphorylation arises to inform therapeutic and biomarker design for tauopathies.

Original languageEnglish
Article numberabl8809
Number of pages15
JournalScience Advances
Volume8
Issue number27
DOIs
Publication statusPublished - 6 Jul 2022

Keywords

  • Hyperphosphorylation
  • neuronal tau protein
  • neurodegenerative tauopathies
  • Alzheimer’s disease

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