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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 α-synuclein. α-synuclein misfolding and oligomer formation is considered a major pathogenic trigger in these disorders. Therefore, targeting α-synuclein species repr...

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Autores principales: Kallab, Martin, Herrera-Vaquero, Marcos, Johannesson, Malin, Eriksson, Fredrik, Sigvardson, Jessica, Poewe, Werner, Wenning, Gregor K., Nordström, Eva, Stefanova, Nadia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039792/
https://www.ncbi.nlm.nih.gov/pubmed/30022929
http://dx.doi.org/10.3389/fnins.2018.00452
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author Kallab, Martin
Herrera-Vaquero, Marcos
Johannesson, Malin
Eriksson, Fredrik
Sigvardson, Jessica
Poewe, Werner
Wenning, Gregor K.
Nordström, Eva
Stefanova, Nadia
author_facet Kallab, Martin
Herrera-Vaquero, Marcos
Johannesson, Malin
Eriksson, Fredrik
Sigvardson, Jessica
Poewe, Werner
Wenning, Gregor K.
Nordström, Eva
Stefanova, Nadia
author_sort Kallab, Martin
collection PubMed
description 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.
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spelling pubmed-60397922018-07-18 Region-Specific Effects of Immunotherapy With Antibodies Targeting α-synuclein in a Transgenic Model of Synucleinopathy Kallab, Martin Herrera-Vaquero, Marcos Johannesson, Malin Eriksson, Fredrik Sigvardson, Jessica Poewe, Werner Wenning, Gregor K. Nordström, Eva Stefanova, Nadia Front Neurosci Neuroscience 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. Frontiers Media S.A. 2018-07-04 /pmc/articles/PMC6039792/ /pubmed/30022929 http://dx.doi.org/10.3389/fnins.2018.00452 Text en Copyright © 2018 Kallab, Herrera-Vaquero, Johannesson, Eriksson, Sigvardson, Poewe, Wenning, Nordström and Stefanova. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Kallab, Martin
Herrera-Vaquero, Marcos
Johannesson, Malin
Eriksson, Fredrik
Sigvardson, Jessica
Poewe, Werner
Wenning, Gregor K.
Nordström, Eva
Stefanova, Nadia
Region-Specific Effects of Immunotherapy With Antibodies Targeting α-synuclein in a Transgenic Model of Synucleinopathy
title Region-Specific Effects of Immunotherapy With Antibodies Targeting α-synuclein in a Transgenic Model of Synucleinopathy
title_full Region-Specific Effects of Immunotherapy With Antibodies Targeting α-synuclein in a Transgenic Model of Synucleinopathy
title_fullStr Region-Specific Effects of Immunotherapy With Antibodies Targeting α-synuclein in a Transgenic Model of Synucleinopathy
title_full_unstemmed Region-Specific Effects of Immunotherapy With Antibodies Targeting α-synuclein in a Transgenic Model of Synucleinopathy
title_short Region-Specific Effects of Immunotherapy With Antibodies Targeting α-synuclein in a Transgenic Model of Synucleinopathy
title_sort region-specific effects of immunotherapy with antibodies targeting α-synuclein in a transgenic model of synucleinopathy
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039792/
https://www.ncbi.nlm.nih.gov/pubmed/30022929
http://dx.doi.org/10.3389/fnins.2018.00452
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