title: Age-dependent defects of alpha-synuclein oligomer uptake in microglia and monocytes.
abstract: Extracellular alpha-synuclein (αsyn) oligomers, associated to exosomes or free, play an important role in the pathogenesis of Parkinson's disease (PD). Increasing evidence suggests that these extracellular moieties activate microglia leading to enhanced neuronal damage. Despite extensive efforts on studying neuroinflammation in PD, little is known about the impact of age on microglial activation and phagocytosis, especially of extracellular αsyn oligomers. Here, we show that microglia isolated from adult mice, in contrast to microglia from young mice, display phagocytosis deficits of free and exosome-associated αsyn oligomers combined with enhanced TNFα secretion. In addition, we describe a dysregulation of monocyte subpopulations with age in mice and humans. Accordingly, human monocytes from elderly donors also show reduced phagocytic activity of extracellular αsyn. These findings suggest that these age-related alterations may contribute to an increased susceptibility to pathogens or abnormally folded proteins with age in neurodegenerative diseases.
authors.affiliation: Department of Neurology, Ulm University, Albert Einstein Allee 11, 89081, Ulm, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Bliederhaeuser
authors.affiliation: Department of Neurology, Ulm University, Albert Einstein Allee 11, 89081, Ulm, Germany.
authors.forename: Veselin
authors.initials: V
authors.lastname: Grozdanov
authors.affiliation: Boehringer Ingelheim Pharma GmbH and Co KG, CNS Diseases Research, Biberach Riss, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Speidel
authors.affiliation: Department of Neurology, Ulm University, Albert Einstein Allee 11, 89081, Ulm, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Zondler
authors.affiliation: Department of Neurology, Ulm University, Albert Einstein Allee 11, 89081, Ulm, Germany.
authors.forename: Wolfgang P
authors.initials: WP
authors.lastname: Ruf
authors.affiliation: Department of Neurology, Ulm University, Albert Einstein Allee 11, 89081, Ulm, Germany.
authors.forename: Hanna
authors.initials: H
authors.lastname: Bayer
authors.affiliation: Department of Neurology, Ulm University, Albert Einstein Allee 11, 89081, Ulm, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Kiechle
authors.affiliation: Department of Neurology, Ulm University, Albert Einstein Allee 11, 89081, Ulm, Germany.
authors.forename: Marisa S
authors.initials: MS
authors.lastname: Feiler
authors.affiliation: Department of Neurology, Ulm University, Albert Einstein Allee 11, 89081, Ulm, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Freischmidt
authors.affiliation: Department of Neurology, Ulm University, Albert Einstein Allee 11, 89081, Ulm, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Brenner
authors.affiliation: Department of Neurology, Ulm University, Albert Einstein Allee 11, 89081, Ulm, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Witting
authors.affiliation: Boehringer Ingelheim Pharma GmbH and Co KG, CNS Diseases Research, Biberach Riss, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Hengerer
authors.affiliation: Institute for Pharmaceutical Biotechnology, Center for Biomedical Research, University of Ulm, Ulm, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Fändrich
authors.affiliation: Department of Neurology, Ulm University, Albert Einstein Allee 11, 89081, Ulm, Germany.
authors.forename: Albert C
authors.initials: AC
authors.lastname: Ludolph
authors.affiliation: Department of Neurology, Ulm University, Albert Einstein Allee 11, 89081, Ulm, Germany.
authors.forename: Jochen H
authors.initials: JH
authors.lastname: Weishaupt
authors.affiliation: Boehringer Ingelheim Pharma GmbH and Co KG, CNS Diseases Research, Biberach Riss, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Gillardon
authors.affiliation: Department of Neurology, Ulm University, Albert Einstein Allee 11, 89081, Ulm, Germany. karin.danzer@uni-ulm.de.
authors.forename: Karin M
authors.initials: KM
authors.lastname: Danzer
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002850:Chromatography, Gel; D004797:Enzyme-Linked Immunosorbent Assay; D055354:Exosomes / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D051379:Mice; D017628:Microglia / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism; D010587:Phagocytosis / Q000502:physiology; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein
keywords: Aging; Alpha-synuclein; Exosomes; Microglia; Monocytes; Parkinson’s disease