Is microglial apoptosis an early pathogenic change in cerebral X-linked adrenoleukodystrophy?
Is microglial apoptosis an early pathogenic change in cerebral X-linked adrenoleukodystrophy?
复制标题
DOI：
10.1002/ana.21391
复制
发表时间：
2008-06-01
影响因子：
11.2
通讯作者：
Ransohoff, Richard M.
中科院分区：
文献类型：
--
作者：
Eichler, Florian S.;Ren, Ja-Qian;Ransohoff, Richard M.
目的：x连锁肾上腺脑白质营养不良（X-ALD）蛋白的突变导致未支化饱和甚长链脂肪酸的积累，特别是在大脑和肾上腺皮质。在人类中，遗传缺陷导致大脑进行性炎性脱髓鞘，其中长链脂肪酸积聚在磷脂组分中，如溶血磷脂酰胆碱。方法：为了解决炎症机制，我们研究了人类ALD（10例尸检）和小鼠顶叶皮层溶血磷脂酰胆碱（C24:0）注射的小胶质细胞激活。结果：出乎意料的是，我们在病灶周围的白质中发现了一个缺乏小胶质细胞的区域，就在主动脱髓鞘病变边缘之外。在这个区域周围，我们观察到皮层下白质中有激活的和凋亡的小胶质细胞簇。小鼠注射溶血磷脂酰胆碱（C24:0）导致广泛的小胶质细胞活化和凋亡。解释：我们的数据表明，在大脑X-ALD中看到的独特的单核吞噬细胞反应，至少部分是由小胶质细胞上的同源受体的异常信号引起的。我们的研究结果支持了一种假设，即病灶周围白质的小胶质细胞凋亡代表了病变演变的早期阶段，可能是有大脑脱髓鞘证据的X-ALD患者干预的合适目标。
Objective: Mutations in the X-linked adrenoleukodystrophy (X-ALD) protein cause accumulation of unbranched saturated very-long-chain fatty acids, particularly in brain and adrenal cortex. In humans, the genetic defect causes progressive inflammatory demyelination in the brain, where very-long-chain fatty acids accumulate within phospholipid fractions such as lysophosphatidylcholine.Methods: To address mechanisms of inflammation, we studied microglial activation in human ALD (10 autopsies) and lysophosphatidylcholine (C24:0) injection into the parietal cortex of mice.Results: Unexpectedly, we found a zone lacking microglia within perilesional white matter, immediately beyond the actively demyelinating lesion edge. Surrounding this zone we observed clusters of activated and apoptotic microglia within subcortical white matter. Lysophosphatidylcholine (C24:0) injection in mice led to widespread microglial activation and apoptosis.Interpretation: Our data suggest that the distinct mononuclear phagocytic cell response seen in cerebral X-ALD results, at least in part, from aberrant signaling to cognate receptors on microglia. Our Findings support a hypothesis that microglial apoptosis in perilesional white matter represents an early stage in lesion evolution and may be an appropriate target for intervention in X-ALD patients with evidence of cerebral demyelination.