小胶质细胞缺乏加速朊病毒病但不增强朊病毒在大脑中的积累

Microglia deficiency accelerates prion disease but does not enhance prion accumulation in the brain

朊病毒病是与朊病毒蛋白错误折叠相关的传染性神经退行性疾病。先前的研究表明,减少小胶质细胞会加速中枢神经系统(CNS)朊病毒病并增加朊病毒在大脑中的积累,这表明小胶质细胞通过吞噬和破坏朊病毒以提供神经保护作用。在Csf1rΔFIRE小鼠中,删除Csf1r中的增强子会特异性地阻止小胶质细胞的发育。然而该小鼠大脑发育正常,并且未显示出如其他小胶质细胞缺陷模型中报道的缺陷。用Csf1rΔFIRE小鼠作为研究小胶质细胞缺乏对中枢神经系统朊病病的影响的改良模型。尽管Csf1rΔFIRE小鼠比野生型小鼠更早地死于CNS朊病毒病,但它们大脑中朊病毒的积累却减少了。而星形胶质细胞则表现出更早的非极化反应性激活,增强了对神经元内容物的吞噬作用和非折叠蛋白质反应。我们的数据表明,小胶质细胞在中枢神经系统朊病毒病中的作用并非简单地吞噬和破坏朊病毒,而是提供宿主保护并限制反应性星形胶质细胞的有害活动。

Prion diseases are transmissible,neurodegenerative disorders associated with misfolding of the prion protein.Previous studies show that reduction of microglia accelerates central nervous system(CNS)prion disease and increases the accumulation of prions in the brain,suggesting that microglia provide neuroprotection by phagocytosing and destroying prions.In Csf1rΔFIRE mice,the deletion of an enhancer within Csf1r specifically blocks microglia development,however,their brains develop normally and show none of the deficits reported in other microglia-deficient models.Csf1rΔFIRE mice were used as a refined model in which to study the impact of microglia-deficiency on CNS prion disease.Although Csf1rΔFIRE mice succumbed to CNS prion disease much earlier than wild-type mice,the accumulation of prions in their brains was reduced.Instead,astrocytes displayed earlier,non-polarized reactive activation with enhanced phagocytosis of neuronal contents and unfolded protein responses.Our data suggest that rather than simply phagocytosing and destroying prions,the microglia instead provide host-protection during CNS prion disease and restrict the harmful activities of reactive astrocytes.