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Accumulation of tau induced in neurites by microglial proinflammatory mediators

Neural Regeneration Unit, Institute of Reconstructive Neurobiology, University Bonn and Hertie-Foundation, Bonn, Germany

¹ Correspondence: Neural Regeneration Unit, Institute of Reconstructive Neurobiology, University Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany. E-mail: hneuman1{at}uni-bonn.de

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-β 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- (TNF-) 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.

Key Words: neuroinflammation • neurodegeneration • cytokines • tumor necrosis factor- • Alzheimer disease