Seeding of protein aggregation causes cognitive impairment in rat model of cortical synucleinopathy
Seeding of protein aggregation causes cognitive impairment in rat model of cortical synucleinopathy
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DOI：
10.1002/mds.27810
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发表时间：
2019-08-26
影响因子：
8.6
通讯作者：
Cenci, M. Angela
中科院分区：
文献类型：
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作者：
Espa, Elena;Clemensson, Erik K. H.;Cenci, M. Angela
皮层α -突触核蛋白病理在帕金森病和路易体痴呆的认知功能障碍的发展中起作用，尽管致病细胞病变仍不清楚。我们的目的是利用新的实验模型来解决大脑皮层中α -突触核蛋白驱动的病理与认知障碍发展之间的因果关系。方法利用病毒载体诱导人α -突触核蛋白在大鼠内侧前额叶皮层神经元过表达。这与在一些动物中接种预先形成的人α -突触核蛋白原纤维相结合。通过对大鼠前额叶认知功能的测试（延迟匹配/不匹配位置和5选择系列反应时间任务）评估大鼠。神经病理模式采用免疫组织化学表征。结果α -突触核蛋白过表达和单独的原纤维种子均未产生任何行为表型。相比之下，联合使用这两种方法在工作记忆、注意力和抑制控制方面产生了显著的损害。所有注射α -突触核蛋白载体的动物在内侧前额叶皮层及其主要投射靶点表现出对人α -突触核蛋白的高免疫反应性。然而，只有当这种过表达与原纤维接种相结合时，动物才会在内侧前额叶皮层及其紧密相连的大脑区域中表现出大量的蛋白酶k抗性和Ser（129）磷酸化的α -突触核蛋白神经元内包裹体。包裹体与目标皮质区域的树突形态扭曲和部分神经元丢失有关。结论：人类α -突触核蛋白皮层过表达不足以产生认知功能障碍，而将这种过表达与原纤维种子结合会产生与人类路易体病相关的认知和组织病理学表型。(c) 2019年国际帕金森和运动障碍学会
Background Cortical alpha-synuclein pathology plays a role in the development of cognitive dysfunction in both Parkinson's disease and dementia with Lewy bodies, although the causative cellular lesions have remained unclear. We aimed to address causal links between alpha-synuclein-driven pathology in the cerebral cortex and the development of cognitive impairments using new experimental models. Methods Neuronal overexpression of human alpha-synuclein was induced in the rat medial prefrontal cortex using viral vectors. This was combined with inoculations of preformed fibrils of human alpha-synuclein in some animals. Rats were evaluated with tests probing prefrontal cognitive functions (delayed matching/nonmatching to position and 5-choice serial reaction time task). Patterns of neuropathology were characterized immunohistochemically. Results Neither alpha-synuclein overexpression nor the fibril seeds alone yielded any behavioral phenotype. In contrast, combining the 2 approaches produced significant impairments in working memory, attention, and inhibitory control. All animals injected with alpha-synuclein vectors exhibited high immunoreactivity for human alpha-synuclein in the medial prefrontal cortex and its primary projection targets. However, only when this overexpression was combined with fibril inoculations did animals exhibit large, proteinase K-resistant and Ser(129)-phosphorylated alpha-synuclein intraneuronal inclusions in the medial prefrontal cortex and its closely interconnected brain regions. The inclusions were associated with distorted dendritic morphologies and partial neuronal loss in the targeted cortical areas. Conclusions Cortical overexpression of human alpha-synuclein is not sufficient to produce cognitive dysfunction, whereas combining this overexpression with fibril seeds yields both cognitive and histopathological phenotypes that are relevant to human Lewy body disease. (c) 2019 International Parkinson and Movement Disorder Society