Neurodegeneration by activation of the microglial complement-phagosome pathway

Liviu Gabriel Bodea, Yiner Wang, Bettina Linnartz-Gerlach, Jens Kopatz, Lasse Sinkkonen, Ruth Musgrove, Tony Kaoma, Arnaud Muller, Laurent Vallar, Donato A. Di Monte, Rudi Balling, Harald Neumann*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

138 Citations (Scopus)

Abstract

Systemic inflammatory reactions have been postulated to exacerbate neurodegenerative diseases via microglial activation. We now demonstrate in vivo that repeated systemic challenge of mice over four consecutive days with bacterial LPS maintained an elevated microglial inflammatory phenotype and induced loss of dopaminergic neurons in the substantia nigra. The same total cumulative LPS dose given within a single application did not induce neurodegeneration. Whole-genome transcriptome analysis of the brain demonstrated that repeated systemic LPS application induced an activation pattern involving the classical complement system and its associated phagosome pathway. Loss of dopaminergic neurons induced by repeated systemic LPS application was rescued in complement C3-deficient mice, confirming the involvement of the complement system in neurodegeneration. Our data demonstrate that a phagosomal inflammatory response of microglia is leading to complement-mediated loss of dopaminergic neurons.

Original languageEnglish
Pages (from-to)8546-8556
Number of pages11
JournalJournal of Neuroscience
Volume34
Issue number25
DOIs
Publication statusPublished - 2014

Keywords

  • Complement
  • Microglia
  • Neurodegeneration
  • Neuroinflammation
  • Phagosome
  • Transcriptome

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