Research Unit Therapy Development, Institute of Clinical Neuroimmunology, Ludwig-Maximilians-Universität München, Munich, Germany.
Nat Med. 2011 Apr;17(4):495-9. doi: 10.1038/nm.2324. Epub 2011 Mar 27.
In multiple sclerosis, a common inflammatory disease of the central nervous system, immune-mediated axon damage is responsible for permanent neurological deficits. How axon damage is initiated is not known. Here we use in vivo imaging to identify a previously undescribed variant of axon damage in a mouse model of multiple sclerosis. This process, termed 'focal axonal degeneration' (FAD), is characterized by sequential stages, beginning with focal swellings and progressing to axon fragmentation. Notably, most swollen axons persist unchanged for several days, and some recover spontaneously. Early stages of FAD can be observed in axons with intact myelin sheaths. Thus, contrary to the classical view, demyelination-a hallmark of multiple sclerosis-is not a prerequisite for axon damage. Instead, focal intra-axonal mitochondrial pathology is the earliest ultrastructural sign of damage, and it precedes changes in axon morphology. Molecular imaging and pharmacological experiments show that macrophage-derived reactive oxygen and nitrogen species (ROS and RNS) can trigger mitochondrial pathology and initiate FAD. Indeed, neutralization of ROS and RNS rescues axons that have already entered the degenerative process. Finally, axonal changes consistent with FAD can be detected in acute human multiple sclerosis lesions. In summary, our data suggest that inflammatory axon damage might be spontaneously reversible and thus a potential target for therapy.
在多发性硬化症中，一种常见的中枢神经系统炎症性疾病，免疫介导的轴突损伤是导致永久性神经功能缺损的原因。目前尚不清楚轴突损伤是如何引发的。在这里，我们使用体内成像技术在多发性硬化症的小鼠模型中鉴定出一种以前未描述的轴突损伤变体。这一过程被称为“局灶性轴突变性”（FAD），其特征是分阶段进行，首先是局灶性肿胀，然后进展为轴突断裂。值得注意的是，大多数肿胀的轴突在数天内保持不变，有些则自发恢复。FAD 的早期阶段可以在髓鞘完整的轴突中观察到。因此，与经典观点相反，脱髓鞘——多发性硬化症的一个标志——不是轴突损伤的先决条件。相反，局灶性轴内线粒体病理学是损伤的最早超微结构标志，它先于轴突形态的变化。分子成像和药理实验表明，巨噬细胞来源的活性氧和氮物种（ROS 和 RNS）可以触发线粒体病理学并引发 FAD。事实上，ROS 和 RNS 的中和可以挽救已经进入退行性过程的轴突。最后，在急性人类多发性硬化症病变中可以检测到与 FAD 一致的轴突变化。总之，我们的数据表明，炎症性轴突损伤可能是自发可逆的，因此可能是治疗的潜在靶点。
