title: Active glycogen synthase kinase-3 and tau pathology-related tyrosine phosphorylation in pR5 human tau transgenic mice.
abstract: We studied underlying pathomechanisms in tauopathies using pR5 mice that express the P301L tau mutation found in familial forms of frontotemporal dementia. In a longitudinal study we investigated the functional status of glycogen synthase kinase-3 and correlated it with the appearance of distinct tau phospho-epitopes. Neurons displaying increases in activating phosphorylation of glycogen synthase kinase-3α/β at tyrosine 279/216 also showed an intense rather than moderate AT8 (phospho-Ser202/Thr205 tau) immunoreactivity, and immunoreactivity for AT100 (phospho-Ser212/Thr214 tau) and phosphorylated Ser422, phospho-epitopes associated with fibrillar tau pathology. These neurons were rare in 8.5-month-old, but numerous in 18.5- and 28-month-old pR5 mice. Two antibodies that detect phosphotyrosine residues more generally only stained these neurons. In contrast, we did not find increased phosphotyrosine in neuronal perikarya of mice with an amyloid-β plaque pathology. Our results suggest a link between increased tyrosine phosphorylation and tau aggregation. They also reveal for the mouse models studied, that tau- rather than an amyloid-β peptide-induced pathology is associated with increased neuronal tyrosine phosphorylation.
authors.affiliation: Institute II for Anatomy, Medical Faculty, University of Cologne, Cologne, Germany. c.koehler@uni-koeln.de
authors.forename: Christoph
authors.initials: C
authors.lastname: Köhler
authors.forename: Maja
authors.initials: M
authors.lastname: Dinekov
authors.forename: Jürgen
authors.initials: J
authors.lastname: Götz
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D024801:Tauopathies / Q000378:metabolism*; D014018:Tissue Distribution; D014443:Tyrosine / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016875:tau Proteins; D014443:Tyrosine; D038362:Glycogen Synthase Kinase 3