German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany.
Centre for Tumour Microenvironment and.
J Clin Invest. 2021 Jan 4;131(1). doi: 10.1172/JCI132727.
Microglia maintain homeostasis in the brain. However, with age, they become primed and respond more strongly to inflammatory stimuli. We show here that microglia from aged mice had upregulated mTOR complex 1 signaling controlling translation, as well as protein levels of inflammatory mediators. Genetic ablation of mTOR signaling showed a dual yet contrasting effect on microglia priming: it caused an NF-κB-dependent upregulation of priming genes at the mRNA level; however, mice displayed reduced cytokine protein levels, diminished microglia activation, and milder sickness behavior. The effect on translation was dependent on reduced phosphorylation of 4EBP1, resulting in decreased binding of eIF4E to eIF4G. Similar changes were present in aged human microglia and in damage-associated microglia, indicating that upregulation of mTOR-dependent translation is an essential aspect of microglia priming in aging and neurodegeneration.
小胶质细胞在大脑中维持着内环境稳态。然而，随着年龄的增长，它们被预先激活，并对炎症刺激反应更强烈。我们在这里表明，来自老年小鼠的小胶质细胞中，控制翻译的 mTOR 复合物 1 信号转导被上调，以及炎症介质的蛋白水平也升高。mTOR 信号的遗传缺失对小胶质细胞的预激活显示出双重但相反的影响：它导致 NF-κB 依赖性的 mRNA 水平上的预激活基因上调；然而，小鼠表现出细胞因子蛋白水平降低、小胶质细胞激活减少和轻度疾病行为。这种对翻译的影响依赖于 4EBP1 的磷酸化减少，导致 eIF4E 与 eIF4G 的结合减少。在衰老的人类小胶质细胞和损伤相关的小胶质细胞中也存在类似的变化，表明 mTOR 依赖性翻译的上调是衰老和神经退行性变中小胶质细胞预激活的一个重要方面。
