Browse

Immunotherapy targeting toll-like receptor 2 alleviates neurodegeneration in models of synucleinopathy by modulating α-synuclein transmission and neuroinflammation

DC Field Value Language
dc.contributor.authorKim, Changyoun-
dc.contributor.authorSpencer, Brian-
dc.contributor.authorRockenstein, Edward-
dc.contributor.authorYamakado, Hodaka-
dc.contributor.authorMante, Michael-
dc.contributor.authorAdame, Anthony-
dc.contributor.authorFields, Jerel A-
dc.contributor.authorMasliah, Deborah-
dc.contributor.authorIba, Michiyo-
dc.contributor.authorLee, He-Jin-
dc.contributor.authorRissman, Robert A-
dc.contributor.authorLee, Seung-Jae-
dc.contributor.authorMasliah, Eliezer-
dc.date.accessioned2018-11-14T02:00:23Z-
dc.date.available2018-11-14T11:01:58Z-
dc.date.issued2018-08-09-
dc.identifier.citationMolecular Neurodegeneration, 13(1):43ko_KR
dc.identifier.issn1750-1326-
dc.identifier.urihttps://hdl.handle.net/10371/143529-
dc.description.abstractBackground
Synucleinopathies of the aging population are an heterogeneous group of neurological disorders that includes Parkinsons 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.
ko_KR
dc.description.sponsorshipThis work was supported by NIH grants (AG047484, BX003040, and AG051839, to RR), the National Research Foundation grant funded by the Korean Government (NRF-2015R1A2A1A10052540 and NRF-2015R1A2A1A15053661, to S-JL), the Korea Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI14C0093, to S-JL), and Seoul National University Hospital (to S-JL)ko_KR
dc.language.isoenko_KR
dc.publisherBioMed Centralko_KR
dc.titleImmunotherapy targeting toll-like receptor 2 alleviates neurodegeneration in models of synucleinopathy by modulating α-synuclein transmission and neuroinflammationko_KR
dc.typeArticleko_KR
dc.contributor.AlternativeAuthor김창윤-
dc.contributor.AlternativeAuthor이희진-
dc.contributor.AlternativeAuthor이승재-
dc.identifier.doi10.1186/s13024-018-0276-2-
dc.language.rfc3066en-
dc.rights.holderThe Author(s).-
dc.date.updated2018-08-12T03:40:05Z-
Appears in Collections:
College of Medicine/School of Medicine (의과대학/대학원)Dept. of Biomedical Sciences (대학원 의과학과)Journal Papers (저널논문_의과학과)
College of Medicine/School of Medicine (의과대학/대학원)Dept. of Medicine (의학과)Journal Papers (저널논문_의학과)
Files in This Item:
  • mendeley

Items in S-Space are protected by copyright, with all rights reserved, unless otherwise indicated.

Browse