Neurodegeneration severity can be predicted from early microglia alterations monitored in vivo in a mouse model of chronic glaucoma.
Neurodegeneration severity can be predicted from early microglia alterations monitored in vivo in a mouse model of chronic glaucoma.
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DOI：
10.1242/dmm.018788
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发表时间：
2015-05
影响因子：
4.3
通讯作者：
Vetter ML
中科院分区：
文献类型：
--
作者：
Bosco A;Romero CO;Breen KT;Chagovetz AA;Steele MR;Ambati BK;Vetter ML
小胶质细胞发挥关键的稳态作用，并以高时空分辨率响应神经元扰动和衰退。因此，所有慢性CNS病理的过程都被局部小胶质细胞增生和小胶质细胞活化所打断，这些都开始于疾病的早期阶段。然而，在早期疾病进展期间使用小胶质细胞的实时监测来预测神经变性严重程度的可能性尚未被探索。由于视网膜允许实时跟踪荧光小胶质细胞在其完整的壁龛，在这里，我们研究了他们的早期变化与后来的视神经神经变性。为了实现这一点，我们使用遗传性青光眼的DBA/2 J小鼠模型，该模型在衰老过程中发展出不同严重程度的进行性视网膜神经节细胞变性，并且代表了研究与人类青光眼相似的视网膜神经节细胞衰退的致病机制的有用模型。我们通过共聚焦扫描激光检眼镜（cSLO）对1至5个月龄的CX 3CR 1 +/GFP小胶质细胞进行体内成像，并定量细胞密度和形态学活化。我们在视神经乳头（ONH）检测到早期小胶质细胞增生，轴突病首先出现，并可以跟踪米诺环素诱导的这种小胶质细胞增生的衰减。我们还观察到异质性和动态模式的早期小胶质细胞激活的视网膜。当对相同的动物进行老化并分析10个月大时视神经病理学的严重程度时，我们发现与3至4个月大时ONH小胶质细胞增生的水平有很强的相关性。 我们的研究结果表明，实时成像和监测青光眼早期视网膜小胶质细胞增生和小胶质细胞活化的时间过程和水平可以作为未来神经变性严重程度的指标。突出显示的文章：这项研究提供了第一个证据表明，在体内监测的时间过程和早期小胶质细胞的动态变化可能作为晚期慢性神经变性的遗传性青光眼小鼠模型的敏感预测。
Microglia serve key homeostatic roles, and respond to neuronal perturbation and decline with a high spatiotemporal resolution. The course of all chronic CNS pathologies is thus paralleled by local microgliosis and microglia activation, which begin at early stages of the disease. However, the possibility of using live monitoring of microglia during early disease progression to predict the severity of neurodegeneration has not been explored. Because the retina allows live tracking of fluorescent microglia in their intact niche, here we investigated their early changes in relation to later optic nerve neurodegeneration. To achieve this, we used the DBA/2J mouse model of inherited glaucoma, which develops progressive retinal ganglion cell degeneration of variable severity during aging, and represents a useful model to study pathogenic mechanisms of retinal ganglion cell decline that are similar to those in human glaucoma. We imaged CX3CR1+/GFP microglial cells in vivo at ages ranging from 1 to 5 months by confocal scanning laser ophthalmoscopy (cSLO) and quantified cell density and morphological activation. We detected early microgliosis at the optic nerve head (ONH), where axonopathy first manifests, and could track attenuation of this microgliosis induced by minocycline. We also observed heterogeneous and dynamic patterns of early microglia activation in the retina. When the same animals were aged and analyzed for the severity of optic nerve pathology at 10 months of age, we found a strong correlation with the levels of ONH microgliosis at 3 to 4 months. Our findings indicate that live imaging and monitoring the time course and levels of early retinal microgliosis and microglia activation in glaucoma could serve as indicators of future neurodegeneration severity. Highlighted Article: This study provides the first evidence that in vivo monitoring of the time course and dynamics of early microglia alterations might serve as sensitive predictors of late chronic neurodegeneration in a mouse model of inherited glaucoma.
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影响因子：
16.6
作者：
通讯作者：
--
影响因子：
16.2
作者：
Burda JE;Sofroniew MV
通讯作者：
Sofroniew MV
影响因子：
2.5
作者：
Bosco, Alejandra;Steele, Michael R.;Vetter, Monica L.
通讯作者：
Vetter, Monica L.
影响因子：
1.2
作者：
Bosco, Alejandra;Romero, Cesar O.;Vetter, Monica L.
通讯作者：
Vetter, Monica L.
DOI：
10.1073/pnas.0913141107
发表时间：
2010-03-16
影响因子：
11.1
作者：
Crish, Samuel D.;Sappington, Rebecca M.;Calkins, David J.
通讯作者：
Calkins, David J.