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

    167 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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