CNS axonal degeneration and transport deficits at the optic nerve head precede structural and functional loss of retinal ganglion cells in a mouse model of glaucoma
CNS axonal degeneration and transport deficits at the optic nerve head precede structural and functional loss of retinal ganglion cells in a mouse model of glaucoma
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DOI：
10.1186/s13024-020-00400-9
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发表时间：
2020-08-27
影响因子：
15.1
通讯作者：
Zode, Gulab S.
中科院分区：
文献类型：
--
作者：
Maddineni, Prabhavathi;Kasetti, Ramesh B.;Zode, Gulab S.
背景青光眼是一种主要的神经退行性疾病，影响全球超过7000万人。由于缺乏适当的动物模型来忠实地复制原发性开角型青光眼（POAG）（青光眼的最常见形式）的所有表型，因此响应于升高的眼内压（IOP）的轴突变性和视网膜病变的早期病理事件是有限的并且不明确。糖皮质激素（GC）诱导的高眼压（OHT）及其相关的医源性开角型青光眼与POAG有许多共同特征。在这里，我们描述了一种新的GC诱导的OHT小鼠模型，用于治疗青光眼性神经变性，并进一步探讨了轴突变性对IOP升高的反应的早期病理事件。方法C57 BL/6 J小鼠眼周注射地塞米松21-醋酸酯（Dex）和空白对照。在OHT的各个阶段检查青光眼表型，包括IOP、流出设施、视网膜神经节细胞（RGC）的结构和功能丧失、视神经（ON）变性、胶质增生和顺行轴突运输缺陷。结果Dex长期给药可导致与POAG患者相似的小鼠青光眼，包括因流出道功能降低和小梁网功能障碍导致的IOP升高、进行性ON变性以及RGCs结构和功能的丧失。IOP的降低挽救了Dex诱导的ON变性和RGC丢失，表明青光眼性神经变性是IOP依赖性的。此外，右旋糖酐诱导的神经变性与星形胶质细胞活化、轴突运输缺陷、ON脱髓鞘、线粒体积聚和视神经头（ONH）区域的免疫细胞浸润相关。我们的研究进一步表明，在Dex处理的小鼠中，ON变性先于RGC的结构和功能丧失。轴突损伤和转运缺陷起始于ONH，并向ON远端和脑中的靶区域（即上级丘）进展。大部分的顺行运输保存在轴突变性的初始阶段（30%的损失）和完全的运输赤字只观察到在ONH在后期阶段的严重轴突变性（50%的损失）。结论ONH的ON变性和转运障碍先于RGC的结构和功能丧失，为青光眼神经元损伤和轴突恢复提供了新的治疗窗口。
Background Glaucoma is a leading neurodegenerative disease affecting over 70 million individuals worldwide. Early pathological events of axonal degeneration and retinopathy in response to elevated intraocular pressure (IOP) are limited and not well-defined due to the lack of appropriate animal models that faithfully replicate all the phenotypes of primary open angle glaucoma (POAG), the most common form of glaucoma. Glucocorticoid (GC)-induced ocular hypertension (OHT) and its associated iatrogenic open-angle glaucoma share many features with POAG. Here, we characterized a novel mouse model of GC-induced OHT for glaucomatous neurodegeneration and further explored early pathological events of axonal degeneration in response to elevated IOP. Methods C57BL/6 J mice were periocularly injected with either vehicle or the potent GC, dexamethasone 21-acetate (Dex) once a week for 10 weeks. Glaucoma phenotypes including IOP, outflow facility, structural and functional loss of retinal ganglion cells (RGCs), optic nerve (ON) degeneration, gliosis, and anterograde axonal transport deficits were examined at various stages of OHT. Results Prolonged treatment with Dex leads to glaucoma in mice similar to POAG patients including IOP elevation due to reduced outflow facility and dysfunction of trabecular meshwork, progressive ON degeneration and structural and functional loss of RGCs. Lowering of IOP rescued Dex-induced ON degeneration and RGC loss, suggesting that glaucomatous neurodegeneration is IOP dependent. Also, Dex-induced neurodegeneration was associated with activation of astrocytes, axonal transport deficits, ON demyelination, mitochondrial accumulation and immune cell infiltration in the optic nerve head (ONH) region. Our studies further show that ON degeneration precedes structural and functional loss of RGCs in Dex-treated mice. Axonal damage and transport deficits initiate at the ONH and progress toward the distal end of ON and target regions in the brain (i.e. superior colliculus). Most of anterograde transport was preserved during initial stages of axonal degeneration (30% loss) and complete transport deficits were only observed at the ONH during later stages of severe axonal degeneration (50% loss). Conclusions These findings indicate that ON degeneration and transport deficits at the ONH precede RGC structural and functional loss and provide a new potential therapeutic window for rescuing neuronal loss and restoring health of damaged axons in glaucoma.