Microglia deficiency accelerates prion disease but does not enhance prion accumulation in the brain.
Microglia deficiency accelerates prion disease but does not enhance prion accumulation in the brain.
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DOI：
10.1002/glia.24244
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发表时间：
2022-11
期刊：
影响因子：
6.2
通讯作者：
Mabbott, Neil A.
中科院分区：
文献类型：
--
作者：
Bradford, Barry M.;McGuire, Lynne, I;Hume, David A.;Pridans, Clare;Mabbott, Neil A.
Pron病是一种可传播的神经退行性疾病，与Pron蛋白的错误折叠有关。先前的研究表明，小胶质细胞的减少加速了中枢神经系统(CNS)的普恩疾病，并增加了普恩在大脑中的积聚，这表明小胶质细胞通过吞噬和破坏普恩来提供神经保护。在CSF1RΔFIRE小鼠中，CSF1R内增强子的缺失特定地阻止了小胶质细胞的发育，然而，他们的大脑发育正常，没有出现其他小胶质细胞缺陷模型中报告的缺陷。以CSF1RΔ火小鼠为改进模型，研究小胶质细胞缺乏对中枢神经系统病毒病的影响。尽管CSF1RΔ火小鼠比野生型小鼠更早死于中枢神经系统Pron病，但它们大脑中Pron的积累减少了。相反，星形胶质细胞表现出更早的、非极化的反应性激活，神经元内容物的吞噬作用和未折叠的蛋白质反应增强。我们的数据表明，小胶质细胞不是简单地吞噬和破坏普恩病毒，而是在中枢神经系统普恩病毒病期间提供宿主保护，并限制反应性星形胶质细胞的有害活动。在完全缺乏小胶质细胞的小鼠中，中枢神经系统病毒病会加速。在没有小胶质细胞的情况下，Pron在大脑中的积累率没有改变。在中枢神经系统病毒病期间，小胶质细胞提供宿主保护，而不依赖于病毒清除。
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 ΔFIRE 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 ΔFIRE mice were used as a refined model in which to study the impact of microglia‐deficiency on CNS prion disease. Although Csf1r ΔFIRE 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. CNS prion disease is accelerated in mice completely lacking microglia. The rate of prion accumulation in the brain was unaltered in absence of microglia. Microglia provide host‐protection during CNS prion disease independent of prion clearance.
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