Department of Neurology, Friedrich-Alexander University Erlangen, Germany.
Acta Neuropathol. 2012 Feb;123(2):247-58. doi: 10.1007/s00401-011-0890-3. Epub 2011 Oct 19.
Brain-derived neurotrophic factor (BDNF) is involved in neuronal and glial development and survival. While neurons and astrocytes are its main cellular source in the central nervous system (CNS), bioactive BDNF is also expressed in immune cells and in lesions of multiple sclerosis and its animal model experimental autoimmune encephalomyelitis (EAE). Previous data revealed that BDNF exerts neuroprotective effects in myelin oligodendrocyte glycoprotein-induced EAE. Using a conditional knock-out model with inducible deletion of BDNF, we here show that clinical symptoms and structural damage are increased when BDNF is absent during the initiation phase of clinical EAE. In contrast, deletion of BDNF later in the disease course of EAE did not result in significant changes, either in the disease course or in axonal integrity. Bone marrow chimeras revealed that the deletion of BDNF in the CNS alone, with no deletion of BDNF in the infiltrating immune cells, was sufficient for the observed effects. Finally, the therapeutic effect of glatiramer acetate, a well-characterized disease-modifying drug with the potential to modulate BDNF expression, was partially reversed in mice in which BDNF was deleted shortly before the onset of disease. In summary, our data argue for an early window of therapeutic opportunity where modulation of BDNF may exert neuroprotective effects in experimental autoimmune demyelination.
脑源性神经营养因子（BDNF）参与神经元和神经胶质的发育和存活。虽然神经元和星形胶质细胞是其在中枢神经系统（CNS）中的主要细胞来源，但生物活性 BDNF 也在免疫细胞中和多发性硬化症及其动物模型实验性自身免疫性脑脊髓炎（EAE）的病变中表达。先前的数据表明，BDNF 在髓鞘少突胶质细胞糖蛋白诱导的 EAE 中发挥神经保护作用。使用具有 BDNF 诱导缺失的条件敲除模型，我们在此表明，当 EAE 的临床起始阶段缺乏 BDNF 时，临床症状和结构损伤会增加。相比之下，EAE 病程后期 BDNF 的缺失并未导致病程或轴突完整性发生显著变化。骨髓嵌合体显示，CNS 中 BDNF 的缺失而浸润免疫细胞中 BDNF 的缺失足以产生观察到的效果。最后，神经保护作用，具有调节 BDNF 表达潜力的一种特征明确的疾病修饰药物，在疾病发作前不久 BDNF 缺失的小鼠中，其治疗效果部分逆转。总之，我们的数据表明，在实验性自身免疫性脱髓鞘中，BDNF 的调节可能具有神经保护作用，存在一个早期的治疗机会窗口。
