title: Hirano bodies differentially modulate cell death induced by tau and the amyloid precursor protein intracellular domain.
abstract: BACKGROUND
  Hirano bodies are actin-rich paracrystalline inclusions found in brains of patients with Alzheimer's disease (AD), frontotemporal dementia (FTD), and in normal aged individuals. Although studies of post-mortem brain tissue provide clues of etiology, the physiological function of Hirano bodies remains unknown. A cell culture model was utilized to study the interactions of mutant tau proteins, model Hirano bodies, and GSK3β in human astrocytoma cells.
  
  
  RESULTS
  Most tau variants showed co-localization with model Hirano bodies. Cosedimentation assays revealed this interaction may be direct, as recombinant purified forms of tau are all capable of binding F-actin. Model Hirano bodies had no effect or enhanced cell death induced by tau in the absence of amyloid precursor protein intracellular domain (AICD). In the presence of AICD and tau, synergistic cell death was observed in most cases, and model Hirano bodies decreased this synergistic cell death, except for forms of tau that caused significant cell death in the presence of Hirano bodies only. A role for the kinase GSK3β is suggested by the finding that a dominant negative form of GSK3β reduces this synergistic cell death. A subset of Hirano bodies in brain tissue of both Alzheimer's disease and normal aged individuals was found to contain tau, with some Hirano bodies in Alzheimer's disease brains containing hyperphosphorylated tau.
  
  
  CONCLUSIONS
  The results demonstrate a complex interaction between tau and AICD involving activation of GSK3β in promoting cell death, and the ability of Hirano bodies to modulate this process.
authors.forename: William
authors.initials: W
authors.lastname: Spears
authors.forename: Matthew
authors.initials: M
authors.lastname: Furgerson
authors.forename: John Michael
authors.initials: JM
authors.lastname: Sweetnam
authors.forename: Parker
authors.initials: P
authors.lastname: Evans
authors.forename: Marla
authors.initials: M
authors.lastname: Gearing
authors.forename: Marcus
authors.initials: M
authors.lastname: Fechheimer
authors.affiliation: Department of Cellular Biology, University of Georgia, Athens, GA 30602, USA. furukawa@uga.edu.
authors.forename: Ruth
authors.initials: R
authors.lastname: Furukawa
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology*; D001254:Astrocytoma / Q000378:metabolism*; D002460:Cell Line; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3