Early neurodegeneration progresses independently of microglial activation by heparan sulfate in the brain of mucopolysaccharidosis IIIB mice.
Early neurodegeneration progresses independently of microglial activation by heparan sulfate in the brain of mucopolysaccharidosis IIIB mice.
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早期神经变性与硫酸乙酰肝素在粘多糖糖化IIIB小鼠大脑中的小胶质细胞激活无关。
DOI：
10.1371/journal.pone.0002296
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发表时间：
2008-05-28
期刊：
影响因子：
3.7
通讯作者：
Heard, Jean-Michel
中科院分区：
文献类型：
--
作者：
Ausseil, Jerome;Desmaris, Nathalie;Bigou, Stephanie;Attali, Ruben;Corbineau, Sebastien;Vitry, Sandrine;Parent, Mathieu;Cheillan, David;Fuller, Maria;Maire, Irene;Vanier, Marie-Therese;Heard, Jean-Michel
IIIB 型粘多糖贮积症是一种导致儿童早发性智力低下的溶酶体贮积病，硫酸乙酰肝素异常寡糖片段的产生与严重的神经病理学和慢性脑炎症有关。我们在这种疾病的小鼠模型中探讨了生化、病理和炎症性疾病之间的因果关系。在细胞培养中，硫酸乙酰肝素寡糖通过 Toll 样受体 4 和衔接蛋白 MyD88 发出信号激活小胶质细胞。第 10 天，在 MPSIIIB 小鼠的大脑皮层中观察到 CD11b 阳性小胶质细胞和编码趋化因子 MIP1α 的 mRNA 表达增加三倍，但在删除 Toll 样受体 4 或接头蛋白 MyD88 表达的 MPSIIIB 小鼠中观察到，这表明 MPSIIIB 中硫酸乙酰肝素寡糖对小胶质细胞的早期启动 老鼠的大脑。与 MPSIIIB 小鼠相比，双突变小鼠的脑炎症发作延迟了几个月，但疾病标志物表达的发作没有变化，表明在没有硫酸乙酰肝素寡糖引发小胶质细胞的情况下，神经退行性过程的进展相似。与年轻小鼠相比，老年 MPSIIIB 小鼠的炎症不受 TLR4/MyD88 缺陷的影响。这些结果表明 HS 寡糖通过 TLR4/MyD88 途径启动小胶质细胞。尽管这种现象是该疾病所固有的，但它并不是神经退行性过程的主要决定因素。尽管独立于 TLR4/MyD88，但炎症仍可能导致疾病晚期的神经变性。结果支持这样的观点：在这种儿科疾病中，神经变性主要是细胞自主的。
In mucopolysaccharidosis type IIIB, a lysosomal storage disease causing early onset mental retardation in children, the production of abnormal oligosaccharidic fragments of heparan sulfate is associated with severe neuropathology and chronic brain inflammation. We addressed causative links between the biochemical, pathological and inflammatory disorders in a mouse model of this disease. In cell culture, heparan sulfate oligosaccharides activated microglial cells by signaling through the Toll-like receptor 4 and the adaptor protein MyD88. CD11b positive microglial cells and three-fold increased expression of mRNAs coding for the chemokine MIP1α were observed at 10 days in the brain cortex of MPSIIIB mice, but not in MPSIIIB mice deleted for the expression of Toll-like receptor 4 or the adaptor protein MyD88, indicating early priming of microglial cells by heparan sulfate oligosaccharides in the MPSIIIB mouse brain. Whereas the onset of brain inflammation was delayed for several months in doubly mutant versus MPSIIIB mice, the onset of disease markers expression was unchanged, indicating similar progression of the neurodegenerative process in the absence of microglial cell priming by heparan sulfate oligosaccharides. In contrast to younger mice, inflammation in aged MPSIIIB mice was not affected by TLR4/MyD88 deficiency. These results indicate priming of microglia by HS oligosaccharides through the TLR4/MyD88 pathway. Although intrinsic to the disease, this phenomenon is not a major determinant of the neurodegenerative process. Inflammation may still contribute to neurodegeneration in late stages of the disease, albeit independent of TLR4/MyD88. The results support the view that neurodegeneration is primarily cell autonomous in this pediatric disease.
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