Ceramide Is Responsible for the Failure of Compensatory Nerve Sprouting in Apolipoprotein E Knock-Out Mice-猫眼课题宝

神经酰胺是导致载脂蛋白 E 敲除小鼠代偿神经萌芽失败的原因

DOI：

发表时间：

2008

期刊：

Journal of Neuroscience

影响因子：

5.3

通讯作者：

中科院分区：

医学1区

文献类型：

作者：

D. Maysinger;M. Holmes;Xianlin Han;R. Epand;E. Pertens;A. Foerster;C. Barlas;D. Holtzman;J. Diamond

载脂蛋白 E (apoE) 是膜合成和神经生长所需的胆固醇和磷脂的关键转运蛋白。我们现在报道，apoE 基因敲除 (KO) 小鼠中，正常神经生长因子 (NGF) 驱动的未受损皮肤伤害性神经的代偿性萌芽实际上不存在。相比之下，被压碎的轴突的独立于 NGF 的再生不受影响。老年野生型小鼠的结果基本相似。在 apoE KO 小鼠中，内源性发芽刺激值得怀疑，因为 NGF 给药诱导了正常发芽；然而，NGF 在去神经支配的皮肤中正常增加，在轴突中正常运输，并导致 trkA、erk1 和 erk2 磷酸化。然而，神经酰胺合成抑制剂伏马菌素 B1 使 apoE KO 小鼠（尽管老年小鼠没有）恢复了发芽。鸟枪法分析揭示了 apoE KO 小鼠 DRG 神经元中各个神经酰胺种类的广泛变化，并且神经酰胺种类 OH_N15:0 的变化使其成为候选的萌芽抑制剂（在 apoE KO 小鼠中增加并通过伏马菌素 B1 标准化）。然而，单个神经酰胺种类对发芽的未知影响，以及它们在 apoE KO 小鼠中变化水平的变异性以及它们如何受到伏马菌素 B1 的影响，支持不同的结论。我们认为，apoE 表达的缺失会改变神经酰胺种类之间的平衡，从而集体抑制代偿性发芽，而伏马菌素 B1 则建立了一种允许发芽的新平衡。无毒的神经酰胺调节剂可能有助于促进神经酰胺种类受到干扰的神经退行性疾病中的出芽和电路修复，从而增加减少神经酰胺诱导的神经元凋亡的益处。

Apolipoprotein E (apoE) is a key transporter of the cholesterol and phospholipids required for membrane synthesis and nerve growth. We now report a virtual absence in apoE knock-out (KO) mice of normal nerve growth factor (NGF)-driven compensatory sprouting of undamaged cutaneous nociceptive nerves. In contrast, NGF-independent regeneration of crushed axons was unaffected. Essentially similar results came from aged wild-type mice. In apoE KO mice, the endogenous sprouting stimulus was suspect, because NGF administration induced normal sprouting; nevertheless, NGF increased normally in denervated skin, transported normally in the axons, and led to phosphorylation of trkA, erk1, and erk2. However, sprouting was restored in apoE KO mice (although not in aged mice) by fumonisin B1, an inhibitor of ceramide synthesis. A shotgun analysis revealed a wide array of changes in individual ceramide species in DRG neurons of apoE KO mice, and the changes for ceramide species OH_N15:0 made it a candidate inhibitor of sprouting (increased in apoE KO mice and normalized by fumonisin B1). Nevertheless, the unknown effects of individual ceramide species on sprouting, as well as the variability of their changed levels in apoE KO mice and how these were affected by fumonisin B1, support a different conclusion. We suggest that absence of apoE expression alters the balance among ceramide species to one that collectively inhibits compensatory sprouting, whereas fumonisin B1 establishes a new balance that allows sprouting. Nontoxic ceramide modulators might usefully promote sprouting and circuitry repair in neurodegenerative disorders in which ceramide species are perturbed, adding to the benefits of reducing ceramide-induced neuronal apoptosis.