Traumatic brain injury-induced axonal phenotypes react differently to treatment
Traumatic brain injury-induced axonal phenotypes react differently to treatment
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DOI：
10.1007/s00401-014-1376-x
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发表时间：
2015-02-01
影响因子：
12.7
通讯作者：
Povlishock, John T.
中科院分区：
文献类型：
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作者：
Hanell, Anders;Greer, John E.;Povlishock, John T.
在轻度创伤性脑损伤（mTBI）后发现了具有不同形态的受损轴突，尽管目前尚不清楚它们是否反映了对损伤的不同反应或代表了病理进展的不同阶段。这使得针对轴突损伤的治疗干预的评估复杂化。为了解决这个问题，我们评估了轴突损伤随着时间的推移在一个明确的轴突人口，同时也评估线粒体通透性转换作为治疗目标。我们利用在皮质神经元中表达黄色荧光蛋白（YFP）的小鼠，将其与缺乏亲环素D（CypD）（线粒体通透性转换孔开放的正调节剂）的小鼠杂交。他们的后代进行mTBI和随后的轴突损伤进行了评估，使用YFP表达和淀粉样前体蛋白（APP）的免疫组织化学，可视化的共聚焦和电子显微镜。YFP+轴突最初发展为单个APP（+）局灶性肿胀（近端球），进展为轴突切断。断开的轴突节段形成单个球（远端球）或多个球（静脉曲张），这是APP（-），其超微结构与持续的沃勒变性一致。CypD基因敲除不能减少近端球的形成，但减少了远端球和静脉曲张的数量，以及与YFP+轴突无关的小的APP（+）胼胝体球的数量。YFP+轴突含有几种病理形态的观察结果表明创伤性轴突损伤的复杂性。CypD基因敲除减少了一些，但不是所有的亚型，这一事实强调了在评估潜在的神经保护策略时，需要适当地表征受损的轴突。
Injured axons with distinct morphologies have been found following mild traumatic brain injury (mTBI), although it is currently unclear whether they reflect varied responses to the injury or represent different stages of progressing pathology. This complicates evaluation of therapeutic interventions targeting axonal injury. To address this issue, we assessed axonal injury over time within a well-defined axonal population, while also evaluating mitochondrial permeability transition as a therapeutic target. We utilized mice expressing yellow fluorescent protein (YFP) in cortical neurons which were crossed with mice which lacked Cyclophilin D (CypD), a positive regulator of mitochondrial permeability transition pore opening. Their offspring were subjected to mTBI and the ensuing axonal injury was assessed using YFP expression and amyloid precursor protein (APP) immunohistochemistry, visualized by confocal and electron microscopy. YFP+ axons initially developed a single, APP(+), focal swelling (proximal bulb) which progressed to axotomy. Disconnected axonal segments developed either a single bulb (distal bulb) or multiple bulbs (varicosities), which were APP(-) and whose ultrastructure was consistent with ongoing Wallerian degeneration. CypD knock-out failed to reduce proximal bulb formation but decreased the number of distal bulbs and varicosities, as well as a population of small, APP(+), callosal bulbs not associated with YFP+ axons. The observation that YFP+ axons contain several pathological morphologies points to the complexity of traumatic axonal injury. The fact that CypD knock-out reduced some, but not all, subtypes highlights the need to appropriately characterize injured axons when evaluating potential neuroprotective strategies.