AUTHOR=Kallab Martin , Herrera-Vaquero Marcos , Johannesson Malin , Eriksson Fredrik , Sigvardson Jessica , Poewe Werner , Wenning Gregor K. , Nordström Eva , Stefanova Nadia TITLE=Region-Specific Effects of Immunotherapy With Antibodies Targeting α-synuclein in a Transgenic Model of Synucleinopathy JOURNAL=Frontiers in Neuroscience VOLUME=12 YEAR=2018 URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2018.00452 DOI=10.3389/fnins.2018.00452 ISSN=1662-453X ABSTRACT=

Synucleinopathies represent a group of neurodegenerative disorders which are characterized by intracellular accumulation of aggregated α-synuclein. α-synuclein misfolding and oligomer formation is considered a major pathogenic trigger in these disorders. Therefore, targeting α-synuclein species represents an important candidate therapeutic approach. Our aim was to analyze the biological effects of passive immunization targeting α-synuclein and to identify the possible underlying mechanisms in a transgenic mouse model of oligodendroglial α-synucleinopathy. We used PLP-α-synuclein mice overexpressing human α-synuclein in oligodendrocytes. The animals received either antibodies that recognize α-synuclein or vehicle. Passive immunization mitigated α-synuclein pathology and resulted in reduction of total α-synuclein in the hippocampus, reduction of intracellular accumulation of aggregated α-synuclein, particularly significant in the spinal cord. Lowering of the extracellular oligomeric α-synuclein was associated with reduction of the density of activated iba1-positive microglia profiles. However, a shift toward phagocytic microglia was seen after passive immunization of PLP-α-synuclein mice. Lowering of intracellular α-synuclein was mediated by autophagy degradation triggered after passive immunization in PLP-α-synuclein mice. In summary, the study provides evidence for the biological efficacy of immunotherapy in a transgenic mouse model of oligodendroglial synucleinopathy. The different availability of the therapeutic antibodies and the variable load of α-synuclein pathology in selected brain regions resulted in differential effects of the immunotherapy that allowed us to propose a model of the underlying mechanisms of antibody-aided α-synuclein clearance.