Intrastriatal alpha-synuclein fibrils in monkeys: spreading, imaging and neuropathological changes
Intrastriatal alpha-synuclein fibrils in monkeys: spreading, imaging and neuropathological changes
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DOI：
10.1093/brain/awz296
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发表时间：
2019-11-01
期刊：
影响因子：
14.5
通讯作者：
Kordower, Jeffrey H.
中科院分区：
文献类型：
--
作者：
Chu, Yaping;Muller, Scott;Kordower, Jeffrey H.
多项研究表明，在啮齿类动物脑内注射α-突触核蛋白可引起帕金森氏病样路易体病变，并伴有明显的黑质纹状体神经变性。本研究评价了外源性α-突触核蛋白预制纤维注射到非人灵长类动物壳核的病理特征。8只食蟹猴接受了单侧壳核内注射α-突触核蛋白预制纤维，4只猴子接受了假手术。在基线、3个月、6个月、9个月、12个月和15个月时，对猴子进行针对多巴胺转运体的I-123-PE2I单光子发射计算机断层扫描。影像显示多巴胺转运体结合量显著增加，这一效应得到了死后免疫组织化学分析的证实，表明多巴胺转运体的上调是早期病理过程的一部分。组织化学和免疫组织化学显示，α-突触核蛋白在壳核注射前形成纤维，在同侧黑质和注射部位附近的黑质内可见磷酸化的α-突触核蛋白阳性的神经元内包涵体。α-突触核蛋白包涵体呈硫代黄素-S阳性，提示α-突触核蛋白预成纤维诱导的包涵体具有类似于帕金森病脑内淀粉样路易小体病理的病理特征。α-突触核蛋白预制的纤维导致同侧黑质的路易病变，与对照组相比，多巴胺能神经元显著减少(-29.30%)。含有α-突触核蛋白包涵体的黑质神经元表现出多巴胺标志物酪氨酸羟基酶和Nurr1的表型下调。综上所述，我们的发现表明，在非人类灵长类动物中，α-突触核蛋白预制纤维诱导了一种突触核病，具有真实的路易氏病理和早期帕金森氏病的黑质纹状体变化。
Several studies have demonstrated that intrastriatal injections of fibrillar alpha-synuclein in rodent brain induced a Parkinson's disease-like propagation of Lewy body pathology with significant nigrostriatal neurodegeneration. This study evaluated the pathological features when exogenous alpha-synuclein preformed fibrils were injected into the putamen of non-human primates. Eight cynomolgus monkeys received unilateral intraputamen injections of alpha-synuclein preformed fibrils and four monkeys received sham surgery. Monkeys were assessed with I-123-PE2I single-photon emission computerized tomography scans targeting the dopamine transprter at baseline, 3, 6, 9, 12, and 15 months. Imaging revealed a robust increase in dopamine transporter binding, an effect confirmed by port-mortem immunohistochemical analyses, suggesting that upregulation of dopamine transporter occurs as part of an early pathological process. Histochemistry and immunohistochemistry revealed that alpha-synuclein preformed fibrils injections into the putamen induced intraneuronal inclusions positive for phosphorylated alpha-synuclein in ipsilateral substantia nigra and adjacent to the injection site. alpha-Synuclein inclusions were thioflavin-S-positive suggesting that the inclusions induced by alpha-synuclein preformed fibrils exhibited pathological properties similar to amyloid-like Lewy body pathology in Parkinson's disease brains. The alpha-synuclein preformed fibrils resulted in Lewy pathology in the ipsilateral substantia nigra with significant reduction (-29.30%) of dopaminergic neurons as compared with controls. Nigral neurons with alpha-synuclein inclusions exhibited a phenotypic downregulation of the dopamine markers tyrosine hydroxylase and Nurr1. Taken together, our findings demonstrate that alpha-synuclein preformed fibrils induce a synucleinopathy in non-human primates with authentic Lewy pathology and nigrostriatal changes indicative of early Parkinson's disease.