Dataset Information

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

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

SUBMITTER: Kallab M

PROVIDER: S-EPMC6039792 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Kallab Martin M Herrera-Vaquero Marcos M Johannesson Malin M Eriksson Fredrik F Sigvardson Jessica J Poewe Werner W Wenning Gregor K GK Nordström Eva E Stefanova Nadia N

Frontiers in neuroscience 20180704

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 ...[more]

PMID: 30022929

Similar Datasets

Project description:BackgroundSynucleinopathies of the aging population are an heterogeneous group of neurological disorders that includes Parkinson's disease (PD) and dementia with Lewy bodies (DLB) and are characterized by the progressive accumulation of α-synuclein in neuronal and glial cells. Toll-like receptor 2 (TLR2), a pattern recognition immune receptor, has been implicated in the pathogenesis of synucleinopathies because TLR2 is elevated in the brains of patients with PD and TLR2 is a mediator of the neurotoxic and pro-inflammatory effects of extracellular α-synuclein aggregates. Therefore, blocking TLR2 might alleviate α-synuclein pathological and functional effects. For this purpose, herein, we targeted TLR2 using a functional inhibitory antibody (anti-TLR2).MethodsTwo different human α-synuclein overexpressing transgenic mice were used in this study. α-synuclein low expresser mouse (α-syn-tg, under the PDGFβ promoter, D line) was stereotaxically injected with TLR2 overexpressing lentivirus to demonstrate that increment of TLR2 expression triggers neurotoxicity and neuroinflammation. α-synuclein high expresser mouse (α-Syn-tg; under mThy1 promoter, Line 61) was administrated with anti-TLR2 to examine that functional inhibition of TLR2 ameliorates neuropathology and behavioral defect in the synucleinopathy animal model. In vitro α-synuclein transmission live cell monitoring system was used to evaluate the role of TLR2 in α-synuclein cell-to-cell transmission.ResultsWe demonstrated that administration of anti-TLR2 alleviated α-synuclein accumulation in neuronal and astroglial cells, neuroinflammation, neurodegeneration, and behavioral deficits in an α-synuclein tg mouse model of PD/DLB. Moreover, in vitro studies with neuronal and astroglial cells showed that the neuroprotective effects of anti-TLR2 antibody were mediated by blocking the neuron-to-neuron and neuron-to-astrocyte α-synuclein transmission which otherwise promotes NFκB dependent pro-inflammatory responses.ConclusionThis study proposes TLR2 immunotherapy as a novel therapeutic strategy for synucleinopathies of the aging population.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets