mTOR-dependent translation amplifies microglia priming in ageing

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 upregulated mammalian target of rapamycin (mTOR) complex 1 signaling regulating translation, as well as cytokine protein levels. Genetic ablation of mTOR signaling showed a dual, yet contrasting effect on microglia priming: it caused an NF-kB-dependent upregulation of priming genes at 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 and increased 4EBP1 expression, resulting in decreased binding of EIF4E to EIF4G. Similar changes were present in aged human microglia and in damage-associated microglia, indicating upregulation of mTOR-dependent translation is an essential step licensing microglia priming in ageing and neurodegeneration. Examination of gene expression profiles in microglia over age in wild-type C57BL/6J mice.小胶质细胞（Microglia）可维持大脑内稳态。然而随着机体衰老，小胶质细胞会发生致敏，并对炎症刺激产生更强的应答反应。本研究发现，衰老小鼠的小胶质细胞中，雷帕霉素靶蛋白复合物1（mTOR complex 1）介导的翻译调控信号通路以及细胞因子蛋白水平均出现上调。对mTOR信号通路进行基因敲除后，其对小胶质细胞致敏产生了双重且相悖的调控效应：该操作在mRNA水平上引发了依赖于核因子κB（NF-κB）的致敏基因上调；但同时，小鼠体内细胞因子蛋白水平降低、小胶质细胞活化程度减弱，且病态行为有所缓解。该翻译调控效应依赖于真核翻译起始因子4E结合蛋白1（4EBP1）的磷酸化水平下调与表达上调，最终导致真核翻译起始因子4E（EIF4E）与真核翻译起始因子4G（EIF4G）的结合能力下降。衰老人类小胶质细胞与损伤相关小胶质细胞中也存在类似变化，这表明依赖于mTOR的翻译上调是衰老与神经退行性变过程中赋予小胶质细胞致敏能力的关键环节。本研究分析了野生型C57BL/6J小鼠小胶质细胞随年龄变化的基因表达谱。