title: Neurodegeneration by activation of the microglial complement-phagosome pathway.
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.
authors.affiliation: Neural Regeneration Group, Institute of Reconstructive Neurobiology, University of Bonn, 53127 Bonn, Germany.
authors.forename: Liviu-Gabriel
authors.initials: LG
authors.lastname: Bodea
authors.affiliation: Neural Regeneration Group, Institute of Reconstructive Neurobiology, University of Bonn, 53127 Bonn, Germany.
authors.forename: Yiner
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Neural Regeneration Group, Institute of Reconstructive Neurobiology, University of Bonn, 53127 Bonn, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Linnartz-Gerlach
authors.affiliation: Neural Regeneration Group, Institute of Reconstructive Neurobiology, University of Bonn, 53127 Bonn, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Kopatz
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4362 Luxembourg.
authors.forename: Lasse
authors.initials: L
authors.lastname: Sinkkonen
authors.affiliation: German Center for Neurodegenerative Diseases, Bonn, Germany, and.
authors.forename: Ruth
authors.initials: R
authors.lastname: Musgrove
authors.affiliation: Genomics Research Unit, CRP-Santé, L-1526, Luxembourg, Luxembourg.
authors.forename: Tony
authors.initials: T
authors.lastname: Kaoma
authors.affiliation: Genomics Research Unit, CRP-Santé, L-1526, Luxembourg, Luxembourg.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Muller
authors.affiliation: Genomics Research Unit, CRP-Santé, L-1526, Luxembourg, Luxembourg.
authors.forename: Laurent
authors.initials: L
authors.lastname: Vallar
authors.affiliation: German Center for Neurodegenerative Diseases, Bonn, Germany, and.
authors.forename: Donato A
authors.initials: DA
authors.lastname: Di Monte
authors.affiliation: Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4362 Luxembourg.
authors.forename: Rudi
authors.initials: R
authors.lastname: Balling
authors.affiliation: Neural Regeneration Group, Institute of Reconstructive Neurobiology, University of Bonn, 53127 Bonn, Germany, hneuman1@uni-bonn.de.
authors.forename: Harald
authors.initials: H
authors.lastname: Neumann
mesh_terms: D000818:Animals; D003167:Complement Activation / Q000502:physiology*; D003176:Complement C3 / Q000378:metabolism*; D003165:Complement System Proteins / Q000502:physiology*; D059290:Dopaminergic Neurons / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D009434:Neural Pathways / Q000502:physiology; D010588:Phagosomes / Q000378:metabolism / Q000473:pathology / Q000502:physiology*
chemical_list: D003176:Complement C3; D003165:Complement System Proteins
keywords: complement; microglia; neurodegeneration; neuroinflammation; phagosome; transcriptome