Central nervous system inflammation is a hallmark of pathogenesis in mouse models of GM1 and GM2 gangliosidosis
Central nervous system inflammation is a hallmark of pathogenesis in mouse models of GM1 and GM2 gangliosidosis
复制标题
DOI：
10.1093/brain/awg089
复制
发表时间：
2003-04-01
期刊：
影响因子：
14.5
通讯作者：
Platt, FM
中科院分区：
文献类型：
--
作者：
Jeyakumar, M;Thomas, R;Platt, FM
已经研究了GM 2神经节苷脂沉积症[Tay-Sachs，迟发型Tay-Sachs（LOTS），Sandhoff]和GM 1神经节苷脂沉积症的小鼠模型，以确定这些疾病是否存在共同的神经炎性成分。在疾病过程中，我们已经：（i）检查了CNS中许多炎症标志物的表达，包括MHC II类、CD 68、CD 11b（CR 3）、7/4、F4/80、硝基酪氨酸、CD 4和CD 8;（ii）分析了细胞因子的产生[肿瘤坏死因子α（TNF α）、转化生长因子（TGF β 1）和白细胞介素1 β（IL 1 β）];和（iii）研究血脑屏障（BBB）完整性。同时检测细胞凋亡动力学、Fas和TNF-R1的表达。在所有有症状的小鼠模型中，观察到局部小胶质细胞活化/扩增和炎性细胞浸润的进行性增加。在Sandhoff和GM 1小鼠中，BBB通透性的改变是明显的，但在LOTS小鼠中不存在。在这些小鼠模型中，进行性CNS炎症与临床体征的发作一致。Sandhoff小鼠模型中的底物减少治疗减缓了CNS中鞘糖脂的蓄积速率，从而延迟了炎症过程和疾病发病机制的发作。这些数据表明，炎症可能在神经节苷脂沉积症的发病机制中起重要作用。
Mouse models of the GM2 gangliosidoses [Tay-Sachs, late onset Tay-Sachs (LOTS), Sandhoff] and GM1 gangliosidosis have been studied to determine whether there is a common neuro-inflammatory component to these disorders. During the disease course, we have: (i) examined the expression of a number of inflammatory markers in the CNS, including MHC class II, CD68, CD11b (CR3), 7/4, F4/80, nitrotyrosine, CD4 and CD8; (ii) profiled cytokine production [tumour necrosis factor alpha (TNFalpha), transforming growth factor (TGFbeta1) and interleukin 1beta (IL1beta)]; and (iii) studied blood-brain barrier (BBB) integrity. The kinetics of apoptosis and the expression of Fas and TNF-R1 were also assessed. In all symptomatic mouse models, a progressive increase in local microglial activation/expansion and infiltration of inflammatory cells was noted. Altered BBB permeability was evident in Sandhoff and GM1 mice, but absent in LOTS mice. Progressive CNS inflammation coincided with the onset of clinical signs in these mouse models. Substrate reduction therapy in the Sandhoff mouse model slowed the rate of accumulation of glycosphingolipids in the CNS, thus delaying the onset of the inflammatory process and disease pathogenesis. These data suggest that inflammation may play an important role in the pathogenesis of the gangliosidoses.