Efficient Uptake and Dissemination of Scrapie Prion Protein by Astrocytes and Fibroblasts from Adult Hamster Brain

Prion infections target neurons and lead to neuronal loss. However, the role of non-neuronal cells in the initiation and spread of infection throughout the brain remains unclear despite the fact these cells can also propagate prion infectivity. To evaluate how different brain cells process scrapie prion protein (PrPres) during acute infection, we exposed neuron-enriched and non-neuronal cell cultures from adult hamster brain to fluorescently-labeled purified PrPres and followed the cultures by live cell confocal imaging over time. Non-neuronal cells present in both types of cultures, specifically astrocytes and fibroblasts, internalized PrPres more efficiently than neurons. PrPres was trafficked to late endosomal/lysosomal compartments and rapidly transported throughout the cell bodies and processes of all cell types, including contacts between astrocytes and neurons. These observations suggest that astrocytes and meningeal fibroblasts play an as yet unappreciated role in prion infections via efficient uptake and dissemination of PrPres.

朊病毒（prion）感染以神经元为靶点并导致神经元丢失。尽管非神经元细胞同样可传播朊病毒感染性，但这类细胞在感染起始及全脑播散过程中所发挥的作用仍未明确。为探究不同脑细胞在急性感染期间如何处理瘙痒病朊病毒蛋白（PrPres），我们将成年仓鼠脑来源的富集神经元细胞培养物与非神经元细胞培养物，暴露于荧光标记的纯化PrPres中，并通过活细胞共聚焦成像对培养物进行实时追踪。两类培养物中存在的非神经元细胞——尤其是星形胶质细胞与成纤维细胞——对PrPres的内化效率显著高于神经元。PrPres被转运至晚期内体/溶酶体区室，并在所有细胞类型的胞体与突起中快速扩散，其中亦包括星形胶质细胞与神经元之间的接触区域。上述结果表明，星形胶质细胞与脑膜成纤维细胞可通过高效摄取并播散PrPres，在朊病毒感染过程中发挥此前未被认知的重要作用。