Alzheimer's disease(AD)is the most common form of dementia worldwide,impairing memory and cognitive functions due to widespread neuronal death.The global incidence of this neurodegenerative disorder is predicted t...Alzheimer's disease(AD)is the most common form of dementia worldwide,impairing memory and cognitive functions due to widespread neuronal death.The global incidence of this neurodegenerative disorder is predicted to increase rapidly in the near future.This growth in prevalence of AD will create a large burden for health systems worldwide.展开更多
The inflammatory microenvironment and neurotoxicity can hinder neuronal regeneration and functional recovery after spinal cord injury.Ruxolitinib,a JAK-STAT inhibitor,exhibits effectiveness in autoimmune diseases,arth...The inflammatory microenvironment and neurotoxicity can hinder neuronal regeneration and functional recovery after spinal cord injury.Ruxolitinib,a JAK-STAT inhibitor,exhibits effectiveness in autoimmune diseases,arthritis,and managing inflammatory cytokine storms.Although studies have shown the neuroprotective potential of ruxolitinib in neurological trauma,the exact mechanism by which it enhances functional recovery after spinal cord injury,particularly its effect on astrocytes,remains unclear.To address this gap,we established a mouse model of T10 spinal cord contusion and found that ruxolitinib effectively improved hindlimb motor function and reduced the area of spinal cord injury.Transcriptome sequencing analysis showed that ruxolitinib alleviated inflammation and immune response after spinal cord injury,restored EAAT2 expression,reduced glutamate levels,and alleviated excitatory toxicity.Furthermore,ruxolitinib inhibited the phosphorylation of JAK2 and STAT3 in the injured spinal cord and decreased the phosphorylation level of nuclear factor kappa-B and the expression of inflammatory factors interleukin-1β,interleukin-6,and tumor necrosis factor-α.Additionally,in glutamate-induced excitotoxicity astrocytes,ruxolitinib restored EAAT2 expression and increased glutamate uptake by inhibiting the activation of STAT3,thereby reducing glutamate-induced neurotoxicity,calcium influx,oxidative stress,and cell apoptosis,and increasing the complexity of dendritic branching.Collectively,these results indicate that ruxolitinib restores glutamate homeostasis by rescuing the expression of EAAT2 in astrocytes,reduces neurotoxicity,and effectively alleviates inflammatory and immune responses after spinal cord injury,thereby promoting functional recovery after spinal cord injury.展开更多
虽然一直以来被认为是同质细胞群,不同脑区的星形胶质细胞在其生理特性方面却仍表现出差异,例如间隙连接偶联、谷氨酸摄取动力学和细胞内Ca2^+响应。最近的体内RNA谱进一步证明成人CNS中星形胶质细胞的分子异质性。星形胶质细胞异质性...虽然一直以来被认为是同质细胞群,不同脑区的星形胶质细胞在其生理特性方面却仍表现出差异,例如间隙连接偶联、谷氨酸摄取动力学和细胞内Ca2^+响应。最近的体内RNA谱进一步证明成人CNS中星形胶质细胞的分子异质性。星形胶质细胞异质性不仅存在于区域间,还存在于区域内。尽管皮质层的特征性层状组织和用于(天体)胶质细胞生成的多个径向神经胶质祖细胞来源,但成人大脑皮质中星形胶质细胞亚群的分子特征和功能特性基本上仍未定义。我们使用两个星形胶质细胞报告小鼠系:eaat2-tdTomato和Bac aldh1l1-eGFP,在皮质内鉴定tdT-eGFP+、tdTlow e GFP+和tdThigh eGFP+星形胶质细胞亚群(以大约1∶7∶2的比例)。tdT-eGFP+星形胶质细胞群选择性地定位于Ⅰ～Ⅱ层,并显示增加的静息膜电位和膜电阻,但降低钾通道Kir4.1的功能表达。我们还通过荧光激活细胞分选(FACS)分离个体星形胶质细胞亚群,并通过RNA-seq检测它们的转录组差异。我们发现tdT-eGFP+星形胶质细胞的全基因组转录谱与tdTlow e GFP+和tdThigh eGFP+星形胶质细胞的全基因组转录谱完全不同。特别地是一些在例如mog、mobp、Iba1和pdgfrα这样的神经胶质细胞中特异性表达的非星形胶质细胞基因,我们也在tdT-eGFP+星形胶质细胞中观察到其表达水平的升高。总体而言,我们的研究揭示了成人皮质星形胶质细胞亚群之间的分子差异,为了解其在成人皮质中的独特功能揭示了新的亮点。展开更多
文摘Alzheimer's disease(AD)is the most common form of dementia worldwide,impairing memory and cognitive functions due to widespread neuronal death.The global incidence of this neurodegenerative disorder is predicted to increase rapidly in the near future.This growth in prevalence of AD will create a large burden for health systems worldwide.
基金supported by the National Natural Science Foundation of China,No.82272484(to XC).
文摘The inflammatory microenvironment and neurotoxicity can hinder neuronal regeneration and functional recovery after spinal cord injury.Ruxolitinib,a JAK-STAT inhibitor,exhibits effectiveness in autoimmune diseases,arthritis,and managing inflammatory cytokine storms.Although studies have shown the neuroprotective potential of ruxolitinib in neurological trauma,the exact mechanism by which it enhances functional recovery after spinal cord injury,particularly its effect on astrocytes,remains unclear.To address this gap,we established a mouse model of T10 spinal cord contusion and found that ruxolitinib effectively improved hindlimb motor function and reduced the area of spinal cord injury.Transcriptome sequencing analysis showed that ruxolitinib alleviated inflammation and immune response after spinal cord injury,restored EAAT2 expression,reduced glutamate levels,and alleviated excitatory toxicity.Furthermore,ruxolitinib inhibited the phosphorylation of JAK2 and STAT3 in the injured spinal cord and decreased the phosphorylation level of nuclear factor kappa-B and the expression of inflammatory factors interleukin-1β,interleukin-6,and tumor necrosis factor-α.Additionally,in glutamate-induced excitotoxicity astrocytes,ruxolitinib restored EAAT2 expression and increased glutamate uptake by inhibiting the activation of STAT3,thereby reducing glutamate-induced neurotoxicity,calcium influx,oxidative stress,and cell apoptosis,and increasing the complexity of dendritic branching.Collectively,these results indicate that ruxolitinib restores glutamate homeostasis by rescuing the expression of EAAT2 in astrocytes,reduces neurotoxicity,and effectively alleviates inflammatory and immune responses after spinal cord injury,thereby promoting functional recovery after spinal cord injury.
文摘虽然一直以来被认为是同质细胞群,不同脑区的星形胶质细胞在其生理特性方面却仍表现出差异,例如间隙连接偶联、谷氨酸摄取动力学和细胞内Ca2^+响应。最近的体内RNA谱进一步证明成人CNS中星形胶质细胞的分子异质性。星形胶质细胞异质性不仅存在于区域间,还存在于区域内。尽管皮质层的特征性层状组织和用于(天体)胶质细胞生成的多个径向神经胶质祖细胞来源,但成人大脑皮质中星形胶质细胞亚群的分子特征和功能特性基本上仍未定义。我们使用两个星形胶质细胞报告小鼠系:eaat2-tdTomato和Bac aldh1l1-eGFP,在皮质内鉴定tdT-eGFP+、tdTlow e GFP+和tdThigh eGFP+星形胶质细胞亚群(以大约1∶7∶2的比例)。tdT-eGFP+星形胶质细胞群选择性地定位于Ⅰ～Ⅱ层,并显示增加的静息膜电位和膜电阻,但降低钾通道Kir4.1的功能表达。我们还通过荧光激活细胞分选(FACS)分离个体星形胶质细胞亚群,并通过RNA-seq检测它们的转录组差异。我们发现tdT-eGFP+星形胶质细胞的全基因组转录谱与tdTlow e GFP+和tdThigh eGFP+星形胶质细胞的全基因组转录谱完全不同。特别地是一些在例如mog、mobp、Iba1和pdgfrα这样的神经胶质细胞中特异性表达的非星形胶质细胞基因,我们也在tdT-eGFP+星形胶质细胞中观察到其表达水平的升高。总体而言,我们的研究揭示了成人皮质星形胶质细胞亚群之间的分子差异,为了解其在成人皮质中的独特功能揭示了新的亮点。
