Priller Josef, Prinz Marco, Heikenwalder Mathias, Zeller Nicolas, Schwarz Petra, Heppner Frank L, Aguzzi Adriano
Institute of Neuropathology, Department of Pathology, University of Zurich, 8091 Zurich, Switzerland.
J Neurosci. 2006 Nov 8;26(45):11753-62. doi: 10.1523/JNEUROSCI.2275-06.2006.
Prion neuroinvasion is accompanied by maximal activation of microglia, the significance of which for pathogenesis is unknown. Here, we used bone marrow (BM) cells expressing GFP (green fluorescent protein) to study the turnover of microglia in mouse scrapie. We found that >or=50% of all brain microglia were replaced by BM-derived cells before clinical disease onset. In terminally sick mice, microglia density increased threefold to fourfold. Hence BM-derived microglia rapidly and efficaciously colonize the brain in scrapie. Whereas reconstitution of wild-type mice with prion protein-deficient (Prnp(o/o)) BM did not alter scrapie pathogenesis, Prnp(o/o) mice transplanted with wild-type BM cells were resistant to peripherally administered prions despite high levels of infectivity in the spleen. Cerebellar homogenates from prion-inoculated Prnp(o/o) mice reconstituted with >10% of wild-type microglia failed to infect transgenic mice overexpressing the cellular prion protein. Hence, in contrast to previous reports, microglia are not competent for efficient prion transport and replication in vivo.
朊病毒神经侵袭伴随着小胶质细胞的最大程度激活，其对发病机制的意义尚不清楚。在此，我们使用表达绿色荧光蛋白（GFP）的骨髓（BM）细胞来研究小鼠瘙痒病中小胶质细胞的更新。我们发现，在临床疾病发作前，所有脑小胶质细胞中≥50%被骨髓来源的细胞所替代。在濒死小鼠中，小胶质细胞密度增加了三到四倍。因此，骨髓来源的小胶质细胞在瘙痒病中能迅速且有效地在脑中定植。用缺乏朊病毒蛋白（Prnp(o/o)）的骨髓重建野生型小鼠并没有改变瘙痒病的发病机制，而移植了野生型骨髓细胞的Prnp(o/o)小鼠尽管脾脏中有高水平的传染性，但对经外周给予的朊病毒具有抗性。用超过10%的野生型小胶质细胞重建的经朊病毒接种的Prnp(o/o)小鼠的小脑匀浆未能感染过表达细胞朊病毒蛋白的转基因小鼠。因此，与先前的报道相反，小胶质细胞在体内不能有效地进行朊病毒运输和复制。
