title: Analysis of ribosomal protein S6 baseline phosphorylation and effect of tau pathology in the murine brain and human hippocampus.
abstract: We examined the distribution pattern of the phosphorylated 40S ribosomal subunit protein S6, a downstream target of the mTOR pathway, in the brains of 24-months-old human tau transgenic pR5 mice, non-transgenic littermates and in human hippocampi. We studied baseline levels of phosphorylated S6 and a possible effect of tau pathology. S6 phosphorylated at Ser235/236 (pS6Ser235/236) or Ser240/244 (pS6Ser240/244) has been used as a read-out of mTOR activity in several studies. The mTOR pathway regulates a wide variety of cellular functions including cell growth, ribosome biosynthesis, translational control and autophagy. Its dysregulation might underlie the neurodegenerative pathology of Alzheimer's disease and other tauopathies. pS6Ser235/236 and pS6Ser240/244 immunoreactivity in the mouse brain were widespread and similar distributed, but intensive pS6Ser235/236 immunoreactivity was more selective, especially highlighting certain brainstem regions. In the human hippocampus mainly granulovacuolar inclusions in neurons displayed pS6Ser235/236 immunoreactivity. In contrast, a considerable number of neurons displayed pS6Ser240/244 immunoreactivity in the cytoplasm without labeling of granulovacuolar inclusions. Except for a tendency of lower numbers of intensely phosphorylated S6-positive neurons in pR5 mice, the pattern of distribution of pS6Ser235/236 and pS6Ser240/244 immunoreactivity was largely unchanged when compared with non-transgenic mice and also when human hippocampi from AD cases and controls were compared. Similar to pR5 mice most neurons with hyper-phosphorylated tau in human hippocampi displayed no or only weak labeling for phosphorylated S6, suggesting that phosphorylated S6 is not especially associated with pathological tau, but is rather a feature of unaffected neurons.
authors.affiliation: Institute II for Anatomy, Medical Faculty, University of Cologne, Kerpener Str. 62, 50924 Cologne, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Klingebiel
authors.affiliation: Institute II for Anatomy, Medical Faculty, University of Cologne, Kerpener Str. 62, 50924 Cologne, Germany.
authors.forename: Maja
authors.initials: M
authors.lastname: Dinekov
authors.affiliation: Institute II for Anatomy, Medical Faculty, University of Cologne, Kerpener Str. 62, 50924 Cologne, Germany. Electronic address: c.koehler@uni-koeln.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Köhler
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D038601:Ribosomal Protein S6 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C054369:MAPT protein, human; C558298:Mapt protein, mouse; D038601:Ribosomal Protein S6; D016875:tau Proteins; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases
keywords: AT100; Alzheimer’s disease; Tauopathy; mTOR