title: IFN-γ promotes τ phosphorylation without affecting mature tangles.
abstract: Inflammatory activation precedes and correlates with accumulating τ lesions in Alzheimer's disease and tauopathies. However, the relationship between neuroinflammation and etiology of pathologic τ remains elusive. To evaluate whether inflammatory signaling may promote or accelerate neurofibrillary tangle pathology, we explored the effect of recombinant adeno-associated virus (rAAV)-mediated overexpression of a master inflammatory cytokine, IFN-γ, on τ phosphorylation. In initial studies in primary neuroglial cultures, rAAV-mediated expression of IFN-γ did not alter endogenous τ production or paired helical filament τ phosphorylation. Next, we tested the effect of rAAV-mediated expression of IFN-γ in the brains of 2 mouse models of tauopathy: JNPL3 and rTg4510. In both models, IFN-γ increased 1) signal transducer and activator of transcription 1 levels and gliosis, and 2) hyperphosphorylation and conformational alterations of soluble τ compared with control cohorts. However, sarkosyl-insoluble phosphorylated τ levels and ubiquitin staining were unaltered in the IFN-γ cohorts. Notably, IFN-γ-induced τ hyperphosphorylation was associated with release of the inhibitory effect of glycogen synthase kinase 3β function by decreasing Ser9 phosphorylation. Our data suggest that type II IFN signaling can promote τ phosphorylation by modulating cellular kinase activity, though this is insufficient in accelerating neuritic tangle pathology.
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, University of Florida, Gainesville, Florida, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Li
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, University of Florida, Gainesville, Florida, USA.
authors.forename: Carolina
authors.initials: C
authors.lastname: Ceballos-Diaz
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, University of Florida, Gainesville, Florida, USA.
authors.forename: Nadia
authors.initials: N
authors.lastname: DiNunno
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, University of Florida, Gainesville, Florida, USA.
authors.forename: Yona
authors.initials: Y
authors.lastname: Levites
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, University of Florida, Gainesville, Florida, USA.
authors.forename: Pedro E
authors.initials: PE
authors.lastname: Cruz
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, University of Florida, Gainesville, Florida, USA.
authors.forename: Jada
authors.initials: J
authors.lastname: Lewis
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, University of Florida, Gainesville, Florida, USA tgolde@ufl.edu pchakrabarty@ufl.edu.
authors.forename: Todd E
authors.initials: TE
authors.lastname: Golde
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, University of Florida, Gainesville, Florida, USA tgolde@ufl.edu pchakrabarty@ufl.edu.
authors.forename: Paramita
authors.initials: P
authors.lastname: Chakrabarty
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D000229:Dependovirus / Q000235:genetics; D004789:Enzyme Activation; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D015151:Immunoblotting; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D016874:Neurofibrillary Tangles / Q000235:genetics / Q000378:metabolism*; D009457:Neuroglia / Q000378:metabolism; D010766:Phosphorylation; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D024801:Tauopathies / Q000235:genetics / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D050794:STAT1 Transcription Factor; D016875:tau Proteins; D007371:Interferon-gamma; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
keywords: GSK3β; interferon-γ; neuroinflammation; τ tangle