Department of Neurology, Wayne State University, Detroit, MI 48201, United States; The Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, United States; Department of Immunology and Microbiology, Wayne State University, Detroit, MI 48201, United States.
J Neuroimmunol. 2013 Sep 15;262(1-2):11-8. doi: 10.1016/j.jneuroim.2013.05.012. Epub 2013 Jun 12.
Soluble factors that promote survival and differentiation of glia and neurons during development are likely to play key roles in neurodegeneration and demyelinating diseases such as multiple sclerosis (MS) and have the potential to be important therapeutic targets. We examined the effect of TrkB signaling and the expression patterns of neurotrophic and gliotrophic factors in the mouse brain in MOG-induced experimental allergic encephalomyelitis (EAE). With induction of mild disease, TrkB heterozygous mice were more severely affected compared to their wild type littermates. However, with more potent disease induction, TrkB heterozygotes fared similar to their wild type littermates, suggesting complex modulatory roles for TrkB signaling. One possible explanation for this difference is that the expression patterns of neurotrophic factors correlate with disease severity in individual mice with mild disease, but not in more severe disease. With the less potent induction in C57BL/6 mice, we found that BDNF was consistently increased at EAE onset, while the soluble gliotrophic factor neuregulin (NRG1) was increased only in the chronic phase of the disease. Treatment of these animals with glatiramer acetate (GA) to decrease disease severity resulted in lower levels of both BDNF and NRG1 expression in some mice at 35days after immunization compared to those in untreated EAE mice, but had no direct effect on these factors in the absence of EAE. Our results suggest a complex interplay between neurotrophic and gliotrophic factors in EAE that is dependent on disease stage and severity. While signaling by BDNF through TrkB is protective in mild disease, this effect was not seen in more severe disease. The late induction of NRG1 in the chronic stage of disease could also worsen disease severity through its known ability to activate microglial, inflammatory pathways. While complex, these studies begin to define underlying axoglial trophic activities that are likely involved in both disease pathogenesis and repair.
在发育过程中促进神经胶质细胞和神经元存活和分化的可溶性因子可能在神经退行性疾病和脱髓鞘疾病（如多发性硬化症）中发挥关键作用，并且有可能成为重要的治疗靶点。我们研究了在实验性自身免疫性脑脊髓炎（EAE）中，TrkB 信号传导和神经营养和神经胶质营养因子的表达模式对小鼠大脑的影响。在诱导轻度疾病时，TrkB 杂合子小鼠比其野生型同窝仔鼠受影响更严重。然而，在更强烈的疾病诱导下，TrkB 杂合子与野生型同窝仔鼠的表现相似，表明 TrkB 信号传导具有复杂的调节作用。这种差异的一个可能解释是，在轻度疾病的个体小鼠中，神经营养因子的表达模式与疾病严重程度相关，但在更严重的疾病中则不相关。在 C57BL/6 小鼠中，我们发现，在 EAE 发病时 BDNF 持续增加，而可溶性神经胶质营养因子神经调节蛋白 1（NRG1）仅在疾病的慢性期增加。用醋酸格拉替雷（GA）治疗这些动物以降低疾病严重程度，与未经治疗的 EAE 小鼠相比，在免疫后 35 天，一些小鼠中的 BDNF 和 NRG1 表达水平降低，但在没有 EAE 的情况下，这些因子对 GA 没有直接影响。我们的结果表明，BDNF 通过 TrkB 信号传导在 EAE 中存在复杂的相互作用，这种相互作用依赖于疾病的阶段和严重程度。虽然 BDNF 通过 TrkB 传递的信号在轻度疾病中具有保护作用，但在更严重的疾病中则没有。在疾病的慢性期，NRG1 的晚期诱导也可能通过其激活小胶质细胞、炎症途径的已知能力使疾病严重程度恶化。尽管这些研究很复杂，但它们开始定义了可能涉及疾病发病机制和修复的潜在轴突胶质营养活性。
