title: Inflammation induces tau pathology in inclusion body myositis model via glycogen synthase kinase-3beta.
abstract: OBJECTIVE
  Inclusion body myositis (IBM) is an inflammatory muscle disease, although the role of inflammation remains to be elucidated. Here, we address the mechanisms by which inflammation modulates Abeta and tau, two hallmark features of this disease.
  
  
  METHODS
  A transgenic mouse model of IBM was utilized in which acute and chronic inflammation was induced via lipopolysaccharide. The effects of inflammation were assessed by analyzing the myopathological and the behavioral phenotype. Human IBM skeletal muscle biopsies were investigated to determine concordance with data from the animal model.
  
  
  RESULTS
  Both acute and chronic lipopolysaccharide exposure augmented infiltration by CD8(+) cytotoxic T cells and increased amyloid precursor protein steady-state levels in skeletal muscle, whereas increased Abeta generation was observed only in chronically treated mice. Both acute and chronic inflammation enhanced tau phosphorylation in skeletal muscle. The mechanism underlying this effect was mediated by the tau kinase, glycogen synthase kinase-3beta (GSK-3beta). Suppression of GSK-3beta activity using either a specific inhibitor or lithium chloride significantly reduced tau phosphorylation and partially rescued motor impairment. In human IBM muscle, GSK-3beta and phospho-tau were colocalized, further supporting the pathogenic role of GSK-3beta in this disease. Using C2C12 myoblast cultures, we found that GSK-3beta was activated by proinflammatory cytokines (interleukin-1beta, interleukin-6, tumor necrosis factor-alpha), leading to enhanced tau phosphorylation.
  
  
  CONCLUSIONS
  Our results identify a molecular mechanism by which proinflammatory stimuli affect tau pathology via the GSK-3beta signaling pathway in skeletal muscle.
authors.affiliation: Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA 92697-4545, USA.
authors.forename: Masashi
authors.initials: M
authors.lastname: Kitazawa
authors.forename: Dan N
authors.initials: DN
authors.lastname: Trinh
authors.forename: Frank M
authors.initials: FM
authors.lastname: LaFerla
mesh_terms: D000818:Animals; D001706:Biopsy; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000276:immunology / Q000494:pharmacology; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000187:drug effects / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007249:Inflammation / Q000201:enzymology* / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000201:enzymology / Q000503:physiopathology*; D018979:Myositis, Inclusion Body / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D010766:Phosphorylation / Q000187:drug effects; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; C080888:tau-protein kinase