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Cell-based Assay to Study Antibody-mediated Tau Clearance by Microglia
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Accumulation of tau induced in neurites by microglial proinflammatory mediators

Philipp Gorlovoy1, Sergey Larionov, Thao Thi Hien Pham

  • 1Neural Regeneration Unit, Institute of Reconstructive Neurobiology, University Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|March 18, 2009
PubMed

Insights

Activated microglia and tumor necrosis factor-alpha (TNF-alpha) induce tau aggregation in neurons. This process involves reactive oxygen species and can be blocked by TNF neutralization or antioxidants.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Biochemistry

Background:

  • Tau protein aggregation into neurofibrillary tangles is central to Alzheimer's disease pathogenesis.
  • The precise molecular triggers for tau aggregation remain elusive.
  • Microglial activation and migration precede neuritic and tangle formation in Alzheimer's disease.

Purpose of the Study:

  • To investigate the role of activated microglia and inflammatory mediators in tau aggregation.
  • To analyze tau accumulation in cultured neurons using advanced imaging techniques.

Main Methods:

  • Utilized fluorescence lifetime-based Förster resonance energy transfer (FRET) in primary murine neurons.
  • Co-cultured neurons with activated microglia or treated with tumor necrosis factor-alpha (TNF-alpha).
  • Quantified tau aggregation in neurites using tau variants tagged with fluorescent proteins (Citrine and Cerulean).

Main Results:

  • No spontaneous tau aggregation was observed in untreated neurons.
  • Coculture with activated microglia induced significant tau aggregation in neuronal neurites.
  • TNF-alpha treatment stimulated reactive oxygen species (ROS) generation and promoted tau accumulation.
  • Inhibition of TNF and ROS generation (using Trolox) prevented tau accumulation.

Conclusions:

  • Activated microglia can induce tau aggregation in neurons.
  • The pro-inflammatory cytokine TNF-alpha, released by microglia, drives tau accumulation via ROS.
  • This study elucidates a key mechanism linking neuroinflammation to tau pathology in Alzheimer's disease.

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