The machanism of oligodendroglial apoptosis of in the model of the genetic demyelination.

抽搐鼠是由半乳糖神经酰胺酶缺乏引起的人类克拉伯病的真实模型。出生后第30天，少突胶质细胞数量进行性减少，导致中枢神经系统脱髓鞘。在本研究中，我们首先通过形态学标准以及tunel阳性的少突胶质细胞和DNA阶梯的存在，发现抽动大脑中少突胶质细胞因凋亡而耗竭。然而，脊髓内的少突胶质细胞可能通过坏死途径而非凋亡途径导致细胞死亡。因此，即使这种基本缺陷对所有的抽动性少突胶质细胞是共同的，环境因素也可能决定它们走向最终死亡的途径。我们还认识到，TNF-α，一个在体外建立的凋亡分子，在抽搐的大脑中与脱髓鞘的进展一致表达，而TNF-α在年龄匹配的正常对照中不表达。双标记显示，TNF-α在抽搐脑活化的小胶质细胞/巨噬细胞中表达，特别是在小脑白质和小脑桥脑角。这些部位严重脱髓鞘，少突胶质细胞大量凋亡。这些证据表明，这些病变中少突胶质细胞的凋亡是通过TNF-α-介导的途径进行的。我们现在正在研究TNF-α诱导活化小胶质细胞的下游级联反应。了解少突胶质细胞死亡的确切机制可以为这种遗传性脱髓鞘提供合理的治疗方法。

The twitcher mouse is an authentic model of a human Krabbe disease, which is caused by the deficiency of galactosylceramidase. After postnatal day 30, the number of oligodendroglia progressive decreased with resultant demyelination in the CNS.In this study, we first found out that oligodendroglia in the twitcher cerebrum were depleted by apoptosis judgeby the morphological criteria as well as the presence of TUNEL-positive oligodendroglia and DNA laddering. However, oligodendroglia in the spinal cord was suggested to take a necrotic pathway rather than apoptosis leading to the cell death. Thus, even if thebasic defect is common to all twitcher oligodendroglia, the environmental factors may decide what pathways they take to the eventual death.We also recognized that TNF-α, a well-established apoptotic molecule in vitro, became expressed in concordance with the progression of demyelination in the twitcher brains, whereas TNF-α is not expressed in the age-matched normal controls. Double labeling revealed that TNF-α was expressed in activated microglia/macrophages in the twitcher brains, especially in the cerebellar white matter and the cerebellopontine angle. These sites were severely demyelinated with a lot of apoptotic oligodendrocytes. These lines of evidence indicated that the apoptosis of oligodendroglia in these lesions was progressed via the TNF-α-mediated pathway. We are now investigating the downstream cascade following the TNF-α induction in activated microglia.To know the exact mechanism how oligodendroglia die may make the rational therapy available for this genetic demyelination.