Microglial dysfunction as a key pathological change in adrenomyeloneuropathy
Microglial dysfunction as a key pathological change in adrenomyeloneuropathy
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DOI：
10.1002/ana.25085
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发表时间：
2017-11-01
影响因子：
11.2
通讯作者：
Eichler, Florian
中科院分区：
文献类型：
--
作者：
Gong, Yi;Sasidharan, Nikhil;Eichler, Florian
目的ABCD1基因突变导致神经退行性疾病-肾上腺脑白质营养不良，在几乎所有存活到成年的男性中都表现为脊髓轴索病肾上腺脊髓神经病变(AMN)。小胶质细胞功能障碍长期以来一直与脑疾病的发病机制有关，但其在脊髓中的作用尚不清楚。方法我们评估了AMN患者和小鼠的脊髓小胶质细胞，并在细胞培养中观察了ABCD1在小胶质细胞吞噬神经元功能中的作用。由于ABCD1基因突变导致超长链脂肪酸进入磷脂，我们分别检测了溶血磷脂酰胆碱(LPC)对小胶质细胞的影响。结果在AMN患者的脊髓中，几个吞噬相关标记物，如MFGE8和TREM2，上调先于补体激活和突触丢失。出乎意料的是，这发生在没有明显炎症的情况下。在培养的ABCD1缺陷的小胶质细胞中加入LPC C26：0进一步增强MFGE8的表达，加重吞噬作用，导致神经元损伤。此外，暴露在MFGE8阻断抗体下会降低吞噬活性。说明缺乏ABCD1的脊髓小胶质细胞为吞噬做好准备，影响代谢环境改变中的神经元。阻断吞噬作用或特异性吞噬受体可减轻突触丢失和轴突变性。Ann Neurol 2017；82：813-827
ObjectiveMutations in ABCD1 cause the neurodegenerative disease, adrenoleukodystrophy, which manifests as the spinal cord axonopathy adrenomyeloneuropathy (AMN) in nearly all males surviving into adulthood. Microglial dysfunction has long been implicated in pathogenesis of brain disease, but its role in the spinal cord is unclear.MethodsWe assessed spinal cord microglia in humans and mice with AMN and investigated the role of ABCD1 in microglial activity toward neuronal phagocytosis in cell culture. Because mutations in ABCD1 lead to incorporation of very-long-chain fatty acids into phospholipids, we separately examined the effects of lysophosphatidylcholine (LPC) upon microglia.ResultsWithin the spinal cord of humans and mice with AMN, upregulation of several phagocytosis-related markers, such as MFGE8 and TREM2, precedes complement activation and synapse loss. Unexpectedly, this occurs in the absence of overt inflammation. LPC C26:0 added to ABCD1-deficient microglia in culture further enhances MFGE8 expression, aggravates phagocytosis, and leads to neuronal injury. Furthermore, exposure to a MFGE8-blocking antibody reduces phagocytic activity.InterpretationSpinal cord microglia lacking ABCD1 are primed for phagocytosis, affecting neurons within an altered metabolic milieu. Blocking phagocytosis or specific phagocytic receptors may alleviate synapse loss and axonal degeneration. Ann Neurol 2017;82:813-827