title: Accumulation of tau induced in neurites by microglial proinflammatory mediators.
abstract: Aggregated fibrillary microtubule-associated protein tau is the major component of neurofibrillary tangles in Alzheimer's disease. The exact molecular mechanism of tau aggregation is unknown. Microglial cell activation and migration toward amyloid-beta plaques precede the appearance of dysmorphic neurites and formation of neurofibrillary tangles. Here, we analyzed the accumulation of tau at a distance range of expected spontaneous aggregation by fluorescence lifetime-based Förster resonance energy transfer in cultured primary murine neurons cotransfected with the human tau gene tagged to the green fluorescent protein variants Citrine (tau-Citrine) and Cerulean (tau-Cerulean). No spontaneous accumulation of cotransfected tau-Citrine and tau-Cerulean was detected in untreated neurons. Coculture of neurons with activated microglia induced aggregation of tau in neurites. Treatment of neurons with tumor necrosis factor-alpha (TNF-alpha) stimulated reactive oxygen species generation and resulted in the accumulation of tau-Citrine and tau-Cerulean in neurites, which was inhibited by neutralization of TNF and the free radical inhibitor 6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid (Trolox). These data demonstrate that activated microglia and the microglial-derived proinflammatory cytokine TNF can induce accumulation of the aggregation-prone tau molecules in neurites via reactive oxygen species.
authors.affiliation: Neural Regeneration Unit, Institute of Reconstructive Neurobiology, University Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Gorlovoy
authors.forename: Sergey
authors.initials: S
authors.lastname: Larionov
authors.forename: Thao Thi Hien
authors.initials: TT
authors.lastname: Pham
authors.forename: Harald
authors.initials: H
authors.lastname: Neumann
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018920:Coculture Techniques; D031541:Fluorescence Resonance Energy Transfer; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000378:metabolism*; D046912:Multiprotein Complexes; D016501:Neurites / Q000378:metabolism*; D016874:Neurofibrillary Tangles / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D018836:Inflammation Mediators; C054369:MAPT protein, human; D046912:Multiprotein Complexes; D017382:Reactive Oxygen Species; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D016875:tau Proteins; D049452:Green Fluorescent Proteins