Immunotherapy targeting toll-like receptor 2 alleviates neurodegeneration in models of synucleinopathy by modulating α-synuclein transmission and neuroinflammation
Abstract Background Synucleinopathies 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 re...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-08-01
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| Series: | Molecular Neurodegeneration |
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| Online Access: | http://link.springer.com/article/10.1186/s13024-018-0276-2 |
| _version_ | 1818291713658060800 |
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| author | Changyoun Kim Brian Spencer Edward Rockenstein Hodaka Yamakado Michael Mante Anthony Adame Jerel Adam Fields Deborah Masliah Michiyo Iba He-Jin Lee Robert A. Rissman Seung-Jae Lee Eliezer Masliah |
| author_facet | Changyoun Kim Brian Spencer Edward Rockenstein Hodaka Yamakado Michael Mante Anthony Adame Jerel Adam Fields Deborah Masliah Michiyo Iba He-Jin Lee Robert A. Rissman Seung-Jae Lee Eliezer Masliah |
| author_sort | Changyoun Kim |
| collection | DOAJ |
| description | Abstract Background Synucleinopathies 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). Methods Two 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. Results We 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. Conclusion This study proposes TLR2 immunotherapy as a novel therapeutic strategy for synucleinopathies of the aging population. |
| first_indexed | 2024-12-13T02:48:27Z |
| format | Article |
| id | doaj.art-dadb293950f74e659342843756240f2d |
| institution | Directory Open Access Journal |
| issn | 1750-1326 |
| language | English |
| last_indexed | 2024-12-13T02:48:27Z |
| publishDate | 2018-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj.art-dadb293950f74e659342843756240f2d2022-12-22T00:02:07ZengBMCMolecular Neurodegeneration1750-13262018-08-0113111810.1186/s13024-018-0276-2Immunotherapy targeting toll-like receptor 2 alleviates neurodegeneration in models of synucleinopathy by modulating α-synuclein transmission and neuroinflammationChangyoun Kim0Brian Spencer1Edward Rockenstein2Hodaka Yamakado3Michael Mante4Anthony Adame5Jerel Adam Fields6Deborah Masliah7Michiyo Iba8He-Jin Lee9Robert A. Rissman10Seung-Jae Lee11Eliezer Masliah12Molecular Neuropathology Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of HealthDepartment Neurosciences, School of Medicine, University of CaliforniaDepartment Neurosciences, School of Medicine, University of CaliforniaDepartment Neurosciences, School of Medicine, University of CaliforniaDepartment Neurosciences, School of Medicine, University of CaliforniaDepartment Neurosciences, School of Medicine, University of CaliforniaDepartment of Pathology, School of Medicine, University of CaliforniaDepartment Neurosciences, School of Medicine, University of CaliforniaMolecular Neuropathology Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of HealthDepartment of Anatomy, School of Medicine, Konkuk UniversityDepartment Neurosciences, School of Medicine, University of CaliforniaDepartment of Biomedical Sciences, Neuroscience Research Institute, and Department of Medicine, Seoul National University College of MedicineMolecular Neuropathology Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of HealthAbstract Background Synucleinopathies 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). Methods Two 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. Results We 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. Conclusion This study proposes TLR2 immunotherapy as a novel therapeutic strategy for synucleinopathies of the aging population.http://link.springer.com/article/10.1186/s13024-018-0276-2Immunotherapyα-synucleinToll-like receptor 2TransmissionNeuroinflammationNeurodegeneration |
| spellingShingle | Changyoun Kim Brian Spencer Edward Rockenstein Hodaka Yamakado Michael Mante Anthony Adame Jerel Adam Fields Deborah Masliah Michiyo Iba He-Jin Lee Robert A. Rissman Seung-Jae Lee Eliezer Masliah Immunotherapy targeting toll-like receptor 2 alleviates neurodegeneration in models of synucleinopathy by modulating α-synuclein transmission and neuroinflammation Molecular Neurodegeneration Immunotherapy α-synuclein Toll-like receptor 2 Transmission Neuroinflammation Neurodegeneration |
| title | Immunotherapy targeting toll-like receptor 2 alleviates neurodegeneration in models of synucleinopathy by modulating α-synuclein transmission and neuroinflammation |
| title_full | Immunotherapy targeting toll-like receptor 2 alleviates neurodegeneration in models of synucleinopathy by modulating α-synuclein transmission and neuroinflammation |
| title_fullStr | Immunotherapy targeting toll-like receptor 2 alleviates neurodegeneration in models of synucleinopathy by modulating α-synuclein transmission and neuroinflammation |
| title_full_unstemmed | Immunotherapy targeting toll-like receptor 2 alleviates neurodegeneration in models of synucleinopathy by modulating α-synuclein transmission and neuroinflammation |
| title_short | Immunotherapy targeting toll-like receptor 2 alleviates neurodegeneration in models of synucleinopathy by modulating α-synuclein transmission and neuroinflammation |
| title_sort | immunotherapy targeting toll like receptor 2 alleviates neurodegeneration in models of synucleinopathy by modulating α synuclein transmission and neuroinflammation |
| topic | Immunotherapy α-synuclein Toll-like receptor 2 Transmission Neuroinflammation Neurodegeneration |
| url | http://link.springer.com/article/10.1186/s13024-018-0276-2 |
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