Molecular Neuropathology Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA.
Department Neurosciences, School of Medicine, University of California, La Jolla, San Diego, CA, 92093, USA.
Mol Neurodegener. 2018 Aug 9;13(1):43. doi: 10.1186/s13024-018-0276-2.
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).
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.
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.
This study proposes TLR2 immunotherapy as a novel therapeutic strategy for synucleinopathies of the aging population.
衰老人口中的突触核蛋白病是一组异质性神经退行性疾病，包括帕金森病（PD）和路易体痴呆（DLB），其特征是α-突触核蛋白在神经元和神经胶质细胞中的进行性积累。模式识别免疫受体 Toll 样受体 2（TLR2）已被牵连到突触核蛋白病的发病机制中，因为 PD 患者的大脑中 TLR2 升高，并且 TLR2 是细胞外α-突触核蛋白聚集体的神经毒性和促炎作用的介导物。因此，阻断 TLR2 可能减轻α-突触核蛋白的病理和功能影响。为此，本文使用功能抑制性抗体（抗-TLR2）靶向 TLR2。
本研究使用了两种不同的人α-突触核蛋白过表达转基因小鼠。使用 TLR2 过表达慢病毒立体定向注射α-突触核蛋白低表达小鼠（α-syn-tg，在 PDGFβ 启动子，D 线），以证明 TLR2 表达的增加引发神经毒性和神经炎症。使用α-synuclein 高表达小鼠（α-Syn-tg；在 mThy1 启动子下，Line 61）给予抗-TLR2，以检查 TLR2 的功能抑制可改善突触核蛋白病动物模型中的神经病理学和行为缺陷。使用α-突触核蛋白传递活细胞监测系统评估 TLR2 在α-突触核蛋白细胞间传递中的作用。
我们证明了抗-TLR2 的给药减轻了 PD/DLB 突触核蛋白转基因小鼠模型中神经元和星形胶质细胞中α-突触核蛋白的积累、神经炎症、神经退行性变和行为缺陷。此外，神经元和星形胶质细胞的体外研究表明，抗-TLR2 抗体的神经保护作用是通过阻断神经元-神经元和神经元-星形胶质细胞的α-突触核蛋白传递介导的，否则会促进 NFκB 依赖性促炎反应。
本研究提出了 TLR2 免疫疗法作为衰老人口中突触核蛋白病的一种新的治疗策略。
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