Region-Specific Effects of Immunotherapy With Antibodies Targeting α-synuclein in a Transgenic Model of Synucleinopathy.

Synucleinopathies represent a group of neurodegenerative disorders which are characterized by intracellular accumulation of aggregated alpha-synuclein. alpha-synuclein misfolding and oligomer formation is considered a major pathogenic trigger in these disorders. Therefore, targeting alpha-synuclein species represents an important candidate therapeutic approach. Our aim was to analyze the biological effects of passive immunization targeting alpha-synuclein and to identify the possible underlying mechanisms in a transgenic mouse model of oligodendroglial alpha-synucleinopathy. We used PLP- alpha-synuclein mice overexpressing human alpha-synuclein in oligodendrocytes. The animals received either antibodies that recognize alpha-synuclein or vehicle. Passive immunization mitigated alpha-synuclein pathology and resulted in reduction of total alpha-synuclein in the hippocampus, reduction of intracellular accumulation of aggregated alpha-synuclein, particularly significant in the spinal cord. Lowering of the extracellular oligomeric alpha-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-alpha-synuclein mice. Lowering of intracellular alpha-synuclein was mediated by autophagy degradation triggered after passive immunization in PLP-alpha-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 alpha-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 alpha-synuclein clearance.