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Neurodegeneration by activated microglia across a nanofiltration membrane

David J Graber1, Abigail Snyder-Keller, David A Lawrence

  • 1School of Public Health, State University at Albany, Albany, NY 12222, USA. David.J.Graber@Dartmouth.Edu

Journal of Biochemical and Molecular Toxicology
|February 11, 2011
PubMed

Insights

Activated microglia release diffusible factors that cause dopamine neuron death, mediated by nitric oxide. This study developed a novel nanofiltration coculture system to identify these neurotoxic mediators in neurodegenerative diseases.

Area of Science:

  • Neuroscience
  • Immunology

Background:

  • Microglia are immune cells in the brain implicated in neurodegenerative diseases.
  • Their exact role in neuron death is not fully understood.
  • Previous studies show neuron loss with activated microglia, but the specific mediators are unclear.

Purpose of the Study:

  • To investigate the role of diffusible, soluble mediators released by activated microglia in dopamine neuron death.
  • To develop a novel coculture system for studying these mediators.

Main Methods:

  • A novel coculture system using nanofiltration membranes (≤350 Da) was developed.
  • Microglia were activated with lipopolysaccharide.
  • Primary ventral mesencephalon cells (dopamine neurons) were cultured separately.
  • Separation of microglia and neurons by the nanofiltering membrane allowed only small molecules to pass.

Main Results:

  • Diffusible products from activated microglia killed dopamine neurons.
  • Larger molecules, including cytokines, could not pass the nanofiltering membrane.
  • Inhibiting nitric oxide synthase prevented neuron loss, indicating nitric oxide's role.

Conclusions:

  • A novel nanofiltration coculture system can identify diffusible neurotoxic factors from microglia.
  • Nitric oxide is a key mediator in microglia-induced dopamine neuron death.
  • This finding contributes to understanding neuroinflammation in neurodegenerative diseases.

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