The Roslin Institute and R(D)SVS, University of Edinburgh, Easter Bush Campus, Midlothian, UK.
Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Queensland, Australia.
Glia. 2022 Nov;70(11):2169-2187. doi: 10.1002/glia.24244. Epub 2022 Jul 19.
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 Csf1r 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. Csf1r mice were used as a refined model in which to study the impact of microglia-deficiency on CNS prion disease. Although Csf1r 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.
朊病毒病是一种可传播的神经退行性疾病，与朊病毒蛋白的错误折叠有关。先前的研究表明，小胶质细胞的减少会加速中枢神经系统（CNS）朊病毒病，并增加大脑中朊病毒的积累，这表明小胶质细胞通过吞噬和破坏朊病毒提供神经保护。在 CSF1R 敲除小鼠中，CSF1R 内增强子的缺失特异性地阻止了小胶质细胞的发育，但它们的大脑发育正常，没有其他小胶质细胞缺失模型中报道的缺陷。CSF1R 敲除小鼠被用作一种改良模型，用于研究小胶质细胞缺失对中枢神经系统朊病毒病的影响。尽管 CSF1R 敲除小鼠比野生型小鼠更早死于中枢神经系统朊病毒病，但它们大脑中的朊病毒积累减少。相反，星形胶质细胞表现出更早的、非极化的反应性激活，增强了对神经元内容物和未折叠蛋白反应的吞噬作用。我们的数据表明，小胶质细胞在中枢神经系统朊病毒病中提供宿主保护，而不是简单地吞噬和破坏朊病毒，并限制反应性星形胶质细胞的有害活性。
