2026-10-15T10:16:52Z https://api.figshare.com/v2/oai

oai:figshare.com:article/20044757 2022-06-11T04:27:31Z category_26209 portal_959 item_type_3 month_year_06_2022

Alzheimer’s disease: Ablating single master site abolishes tau hyperphosphorylation Kristie Stefanoska (12840116) Arne Ittner (337884) Mehul Gajwani (12840119) Amanda RP Tan (12840122) Holly Ahel (12840125) Prita Asih (7487609) Alexander Volkerling (3220491) Anne Poljak (158842) Other education not elsewhere classified Medical and health sciences 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. <h3>Methods</h3> Raw Immunoblot data for Figure 1. Chemiluninescence signals were imaged on a ChemiDoc MP (Biorad) digital system. 2022-05-13T00:00:00Z Dataset Dataset 10.5061/dryad.bvq83bkc0 https://figshare.com/articles/dataset/Alzheimer_s_disease_Ablating_single_master_site_abolishes_tau_hyperphosphorylation/20044757 CC0