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Age-dependent defects of alpha-synuclein oligomer uptake in microglia and monocytes

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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.

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Acknowledgments

The excellent technical assistance of Ramona Langohr and Irma Merdian is gratefully acknowledged. We thank Simon Moussaud and Pamela J. McLean for providing us the stably αsyn overexpressing H4 cells. Furthermore, we thank Gerd Wandhoff, Christine Wandhoff and Kameliya Petrova for collecting blood samples. This research was supported by funds from the Baustein Program Medical Faculty Ulm University (KMD, VG), the Virtual Helmholtz Institute “RNA dysmetabolims in FTD and ALS” of the Deutsches Zentrum für Neurodegenerative Erkrankungen (AW, HB), Charcot Foundation (AF, LZ, ACL, JHW), Juniorprofessorship Programme Baden-Württemberg (KMD, MK) and the Boehringer Ingelheim Ulm University Biocenter (KMD, CB).

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    1. Department of Neurology, Ulm University, Albert Einstein Allee 11, 89081, Ulm, Germany

      Corinna Bliederhaeuser, Veselin Grozdanov, Lisa Zondler, Wolfgang P. Ruf, Hanna Bayer, Martin Kiechle, Marisa S. Feiler, Axel Freischmidt, David Brenner, Anke Witting, Albert C. Ludolph, Jochen H. Weishaupt & Karin M. Danzer

    2. Boehringer Ingelheim Pharma GmbH and Co KG, CNS Diseases Research, Biberach Riss, Germany

      Anna Speidel, Bastian Hengerer & Frank Gillardon

    3. Institute for Pharmaceutical Biotechnology, Center for Biomedical Research, University of Ulm, Ulm, Germany

      Marcus Fändrich

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    Corinna Bliederhaeuser and Veselin Grozdanov have contributed equally.

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    Bliederhaeuser, C., Grozdanov, V., Speidel, A. et al. Age-dependent defects of alpha-synuclein oligomer uptake in microglia and monocytes. Acta Neuropathol 131, 379–391 (2016). https://doi.org/10.1007/s00401-015-1504-2

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