Compromised Axon Initial Segment Integrity in EAE Is Preceded by Microglial Reactivity and Contact
Compromised Axon Initial Segment Integrity in EAE Is Preceded by Microglial Reactivity and Contact
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DOI：
10.1002/glia.22991
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发表时间：
2016-07-01
期刊：
影响因子：
6.2
通讯作者：
Dupree, Jeffrey L.
中科院分区：
文献类型：
--
作者：
Clark, Kareem C.;Josephson, Anna;Dupree, Jeffrey L.
轴突病变是多发性硬化症（MS）长期残疾的关键因素，MS是一种中枢神经系统（CNS）的炎症性脱髓鞘疾病，但MS中轴突病变的潜在机制仍然难以捉摸。有证据表明轴突病变是脱髓鞘的直接后果，因为我们和其他人已经表明，在髓鞘缺失后，郎飞结会解体。与郎飞结相反，我们现在表明，轴突起始段（AIS），即负责动作电位起始的轴突区域，在双环己酮草酰二腙诱导的皮质脱髓鞘后仍然完整。相反，我们发现AIS在发生实验性自身免疫性脑脊髓炎（EAE）的小鼠新皮质中被破坏，且与局部脱髓鞘无关。EAE诱导的小鼠表现出AIS完整性的严重受损，其进行性破坏与EAE临床疾病的严重程度和持续时间以及皮质小胶质细胞的反应性相对应。此外，用地达诺辛治疗导致AIS病变减轻，同时小胶质细胞恢复到反应性较低的状态。总之，我们的研究结果表明，炎症而非脱髓鞘破坏了AIS的完整性，并且治疗干预可能保护和逆转这种病变。
Axonal pathology is a key contributor to long-term disability in multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS), but the mechanisms that underlie axonal pathology in MS remain elusive. Evidence suggests that axonal pathology is a direct consequence of demyelination, as we and others have shown that the node of Ranvier disassembles following loss of myelin. In contrast to the node of Ranvier, we now show that the axon initial segment (AIS), the axonal domain responsible for action potential initiation, remains intact following cuprizone-induced cortical demyelination. Instead, we find that the AIS is disrupted in the neocortex of mice that develop experimental autoimmune encephalomyelitis (EAE) independent of local demyelination. EAE-induced mice demonstrate profound compromise of AIS integrity with a progressive disruption that corresponds to EAE clinical disease severity and duration, in addition to cortical microglial reactivity. Furthermore, treatment with the drug didox results in attenuation of AIS pathology concomitantly with microglial reversion to a less reactive state. Together, our findings suggest that inflammation, but not demyelination, disrupts AIS integrity and that therapeutic intervention may protect and reverse this pathology.