衰老的脊髓小胶质细胞呈现表型异质并倾向性靶向运动神经元及其突触  

Aging spinal cord microglia become phenotypically heterogeneous and preferentially target motor neurons and their synapses

作　　者：Ryan W Castro Mikayla C Lopes Lindsay M De Biase Gregorio Valdez 杜一星(编译) 

机构地区：[1]Neuroscience Graduate Program,Brown University,Providence,Rhode Island,USA. [2]Molecular Biology,Cell Biology&Biochemistry Graduate Program,Brown University,Providence,Rhode Island,USA. [3]Department of Physiology,David Geffen School of Medicine at UCLA,Los Angeles,California,USA. [4]Department of Molecular Biology,Cell Biology and Biochemistry,Brown University,Providence,Rhode Island,USA. [5]Center for Translational Neuroscience,Robert J.and Nancy D.Carney Institute for Brain Science,and Center on the Biology of Aging,Brown University,Providence,Rhode Island,USA. [6]不详

出　　处：《神经损伤与功能重建》2023年第11期F0003-F0003,共1页Neural Injury and Functional Reconstruction

摘　　要：研究发现小胶质细胞随着年龄的增长和疾病的不同而获得独特的区域依赖性有害特征,从而导致神经元功能障碍和大脑退化。然而,目前尚不清楚脊髓中的小胶质细胞是否表现出类似的表型异质性。本研究对3、16、23和30个月大的小鼠的脊髓小胶质细胞进行区域分析。我们使用光学和电子显微镜发现脊髓小胶质细胞在衰老过程中获得越来越活跃的表型,且该现象与区域无关。然而,衰老会导致腹侧而非背角的小胶质细胞失去其空间组织。衰老的腹角小胶质细胞也会聚集在运动神经元胞体周围,它们与运动神经元突触的接触增加;而运动神经元突触已被证明会随着年龄的增长而消失。这些发现表明,在衰老过程中小胶质细胞可能会影响运动神经元接收和传递运动命令的能力。为了更深入地研究衰老脊髓小胶质细胞,我们对FACS分离的3、18、22和29个月大小鼠的小胶质细胞进行RNA测序。我们发现,脊髓小胶质细胞在衰老过程中获得与大脑中小胶质细胞相似的转录特性,其中包括在小胶质细胞-神经元相互作用和炎症中发挥作用的基因表达的改变。到29个月大时,脊髓小胶质细胞表现出额外且独特的转录变化,已知并预计会导致衰老并改变溶酶体和核糖体调节。总之,这项工作为靶向小胶质细胞以改善脊髓中与衰老相关的变化,特别是运动回路的变化奠定了基础。Microglia have been found to acquire unique region-dependent deleterious features with age and diseases that contribute to neuronal dysfunction and degeneration in the brain.However,it remains unknown whether microg-lia exhibit similar phenotypic heterogeneity in the spinal cord.Here,we performed a regional analysis of spinal cord microglia in 3-,16-,23-,and 30-month-old mice.Using light and electron microscopy,we discovered that spinal cord microglia acquire an increasingly activated phenotype during the course of aging regardless of regional location.However,aging causes microglia in the ventral but not dorsal horn to lose their spatial organization.Aged ventral horn microglia also aggregate around the somata of motor neurons and increase their contacts with motor synapses,which have been shown to be lost with age.These findings suggest that microglia may affect the ability of motor neu-rons to receive and relay motor commands during aging.To generate additional insights about aging spinal cord mi-croglia,we performed RNA-sequencing on FACS-isolated microglia from 3-,18-,22-,and 29-month-old mice.We found that spinal cord microglia acquire a similar transcriptional identity as those in the brain during aging that in-cludes altered expression of genes with roles in microglia-neuron interactions and inflammation.By 29 months of age,spinal cord microglia exhibit additional and unique transcriptional changes known and predicted to cause senes-cence and to alter lysosomal and ribosomal regulation.Altogether,this work provides the foundation to target microg-lia to ameliorate aged-related changes in the spinal cord,and particularly on the motor circuit.

关 键 词：衰老 小胶质细胞 运动神经元 脊髓 突触 

分 类 号：R741[医药卫生—神经病学与精神病学] R741.02[医药卫生—临床医学]