4.7 Article

Accumulation of tau induced in neurites by microglial proinflammatory mediators

Journal

FASEB JOURNAL
Volume 23, Issue 8, Pages 2502-2513

Publisher

FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.08-123877

Keywords

neuroinflammation; neurodegeneration; cytokines; tumor necrosis factor-alpha; Alzheimer disease

Funding

  1. Hertie-Foundation
  2. Walter-und-Ilse-Rose-Foundation
  3. Deutsche Forschungsgemeinschaft [SFB704, KFO177]
  4. European Union (NeuroproMiSe)

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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 Forster 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.-Gorlovoy, P., Larionov, S., Pham, T. T. H., Neumann, H. Accumulation of tau induced in neurites by microglial proinflammatory mediators. FASEB J. 23, 2502-2513 (2009)

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