Proteomic anaysis of aged microglia: shifts in transcription, bioenergetics, and nutrient response.
Proteomic anaysis of aged microglia: shifts in transcription, bioenergetics, and nutrient response.
复制标题
DOI：
10.1186/s12974-017-0840-7
复制
发表时间：
2017-05-03
影响因子：
9.3
通讯作者：
Bickford PC
中科院分区：
文献类型：
--
作者：
Flowers A;Bell-Temin H;Jalloh A;Stevens SM Jr;Bickford PC
年龄是许多疾病的主要危险因素。因此，年龄是检查的关键辅助因素，以了解疾病进展和潜在的干预措施。检查老年小胶质细胞的表型和转录组的研究表明了促炎表型发展的倾向。较少研究的是随着年龄的增长，小胶质细胞功能的抗炎方面也会影响CNS的可塑性和修复。本研究利用基于质谱的蛋白质组学比较年轻和老年动物的初级小胶质细胞。这项研究揭示了三个相互关联的蛋白质簇的变化。这三种途径是炎症信号传导、线粒体功能和细胞代谢。对这些簇的分析确定了mTOR的蛋白质雷帕霉素不敏感伴侣（RICTOR），mTORC 2复合物的一个组分，作为几种生物学功能的新型上游调节因子，这些生物学功能随着年龄的变化而改变，并可能与表型发育有关。通过胰岛素生长因子（IGF）治疗评估，在老年小胶质细胞中观察到mTORC 2依赖性AKT S473磷酸化的减少。这一新的发现得到了小胶质细胞系基因操作的证实。具有减少的RICTOR的BV 2细胞显示出与老年小胶质细胞惊人相似的表型。这一发现特别相关，因为mTOR通路已经有许多临床使用的药理学调节剂。结果表明，来自老年小鼠的小胶质细胞显示出细胞代谢和能量调节的变化，这可能是炎症信号改变的基础。在我们的生物信息学分析中确定的一种途径RICTOR的调节可能提供一种途径，通过该途径可以减弱老化小胶质细胞的有害方面。如果成功，这可能意味着可能延迟或减少涉及进行性炎症的疾病的进展。本文的在线版本（doi：10.1186/s12974-017-0840-7）包含补充材料，可供授权用户使用。
Age is the primary risk factor for many diseases. As such, age is a critical co-factor for examination in order to understand the progression and potential intervention in disease progression. Studies examining both the phenotype and transcriptome of aged microglia demonstrated a propensity for the development of a pro-inflammatory phenotype. Less well studied is the concomitant blunting of anti-inflammatory aspects of microglial function with age which also impact plasticity and repair in the CNS. This study utilizes mass spectrometry-based proteomics to compare primary microglia from young and aged animals. This study revealed alterations in three clusters of inter-related proteins. The three pathways were inflammatory signaling, mitochondrial function, and cellular metabolism. Analysis of these clusters identified the protein rapamycin-insensitive companion of mTOR (RICTOR), a component of the mTORC2 complex, as a novel upstream regulator of several biological functions that are altered with age and potentially linked to phenotype development. A decrease in mTORC2-dependent AKT S473 phosphorylation, as assessed by insulin growth factor (IGF) treatment, was observed in aged microglia. This novel finding was confirmed by genetic manipulation of the microglial cell line. BV2 cells with diminished RICTOR displayed a phenotype that was strikingly similar to that of aged microglia. This finding is particularly relevant as the mTOR pathway already has a number of pharmacological modulators used clinically. The results suggest that microglia from aged mice show changes in cellular metabolism and energy regulation that might underlie the alterations in inflammatory signaling. Modulation of one pathway identified in our bioinformatic analysis, RICTOR, may provide an avenue by which deleterious aspects of the aging microglia can be attenuated. If successful, this could mean potentially delaying or diminishing the progress of diseases for which progressive inflammation is involved. The online version of this article (doi:10.1186/s12974-017-0840-7) contains supplementary material, which is available to authorized users.