Laboratory of Neuroanatomy and Experimental Neurology, Department of Morphological Sciences, Centro de Investigación en Medicina Molecular y Enfermedades Crónicas, Faculty of Medicine, University of Santiago de Compostela, 15782, Santiago de Compostela, Spain.
Networking Research Center on Neurodegenerative Diseases (Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas), Madrid, 28031, Spain.
Neurotherapeutics. 2018 Oct;15(4):1063-1081. doi: 10.1007/s13311-018-0646-z.
The loss of dopaminergic neurons and α-synuclein accumulation are major hallmarks of Parkinson's disease (PD), and it has been suggested that a major mechanism of α-synuclein toxicity is microglial activation. The lack of animal models that properly reproduce PD, and particularly the underlying synucleinopathy, has hampered the clarification of PD mechanisms and the development of effective therapies. Here, we used neurospecific adeno-associated viral vectors serotype 9 coding for either the wild-type or mutated forms of human alpha-synuclein (WT and SynA53T, respectively) under the control of a synapsin promoter to further induce a marked dopaminergic neuron loss together with an important microglial neuroinflammatory response. Overexpression of neuronal alpha-synuclein led to increased expression of angiotensin type 1 receptors and NADPH oxidase activity, together with a marked increase in the number of OX-6-positive microglial cells and expression of markers of phagocytic activity (CD68) and classical pro-inflammatory/M1 microglial phenotype markers such as inducible nitric oxide synthase, tumor necrosis factor alpha, interleukin-1β, and IL-6. Moreover, a significant decrease in the expression of markers of immunoregulatory/M2 microglial phenotype such as the enzyme arginase-1 was constantly observed. Interestingly, alpha-synuclein-induced changes in microglial phenotype markers and dopaminergic neuron death were inhibited by simultaneous treatment with the angiotensin type 1 blockers candesartan or telmisartan. Our results suggest the repurposing of candesartan and telmisartan as a neuroprotective strategy for PD.
多巴胺能神经元的丧失和α-突触核蛋白的积累是帕金森病(PD)的主要标志,并且已经提出α-突触核蛋白毒性的主要机制是小胶质细胞的激活。缺乏适当再现 PD 的动物模型,特别是潜在的突触核蛋白病,阻碍了 PD 机制的阐明和有效治疗方法的发展。在这里,我们使用神经特异性腺相关病毒载体血清型 9,在突触蛋白启动子的控制下,分别编码野生型和突变型人α-突触核蛋白(WT 和 SynA53T),进一步诱导明显的多巴胺能神经元丧失以及重要的小胶质细胞神经炎症反应。神经元α-突触核蛋白的过表达导致血管紧张素 1 型受体和 NADPH 氧化酶活性的增加,同时 OX-6 阳性小胶质细胞的数量和吞噬活性标志物(CD68)以及经典促炎/M1 小胶质细胞表型标志物的表达(诱导型一氧化氮合酶、肿瘤坏死因子-α、白细胞介素-1β 和白细胞介素-6)显著增加。此外,持续观察到免疫调节/M2 小胶质细胞表型标志物的表达,如酶精氨酸酶-1 的显著减少。有趣的是,用血管紧张素 1 型阻滞剂坎地沙坦或替米沙坦同时治疗可抑制α-突触核蛋白诱导的小胶质细胞表型标志物和多巴胺能神经元死亡的变化。我们的结果表明坎地沙坦和替米沙坦可作为 PD 的神经保护策略重新利用。