Wicking Dementia Research and Education Centre, University of Tasmania, Private Bag 23, Hobart, Tasmania 7000, Australia.
Acta Neuropathol Commun. 2013 Sep 9;1:59. doi: 10.1186/2051-5960-1-59.
Axon degeneration, a key pathological event in many neurodegenerative diseases and injury, can be induced by somatodendritic excitotoxin exposure. It is currently unclear, however, whether excitotoxin-induced axon degeneration is mechanistically similar to Wallerian degeneration, which occurs following axon transection, but does not involve axonal caspase activation.
We have used mouse primary cortical neurons at 9 days in vitro, in a compartmented culture model that allows separation of the axon from the soma, to examine the pathological cascade of excitotoxin-induced axon degeneration. Excitotoxicity induced by chronic exposure to kainic acid, resulted in axonal fragmentation, which was associated with activation of caspase-3 in the axonal compartment. To examine the role of microtubules in these events, the microtubule-stabilizing agent, taxol, was added to either the axonal or somatodendritic compartment. Our results demonstrated that microtubule stabilization of axons resulted in a significant reduction in the number of fragmented axons following excitotoxin exposure. Interestingly, taxol exposure to either the somatodendritic or axonal compartment resulted in reduced caspase-3 activation in axons, suggesting that caspase activation is a downstream event of microtubule destabilization and involves signalling from the cell soma.
These data suggest that excitotoxin-induced axon degeneration shows some mechanistic differences to Wallerian degeneration, and that microtubule stabilization may assist in protecting nerve cells from excitotoxic effects.
轴突变性是许多神经退行性疾病和损伤的关键病理事件，可通过体树突兴奋性毒素暴露诱导。然而，目前尚不清楚兴奋性毒素诱导的轴突变性在机制上是否与轴突横断后发生的沃勒变性相似，沃勒变性不涉及轴突半胱天冬酶的激活。
我们使用体外培养 9 天的小鼠原代皮质神经元，在分隔培养模型中，将轴突与胞体分离，以研究兴奋性毒素诱导的轴突变性的病理级联。慢性暴露于红藻氨酸导致轴突碎片化，这与轴突隔中 caspase-3 的激活有关。为了研究微管在这些事件中的作用，将微管稳定剂紫杉醇添加到轴突或树突-胞体隔中。我们的结果表明，轴突微管稳定化导致兴奋性毒素暴露后碎片化轴突的数量显著减少。有趣的是，紫杉醇暴露于树突-胞体或轴突隔均导致轴突中 caspase-3 的激活减少，表明 caspase 激活是微管不稳定的下游事件，涉及来自细胞体的信号转导。
这些数据表明，兴奋性毒素诱导的轴突变性与沃勒变性在机制上存在一些差异，微管稳定化可能有助于保护神经细胞免受兴奋性毒素的影响。
