Chronic Microglial Activation in the GFAP-IL6 Mouse Contributes to Age-Dependent Cerebellar Volume Loss and Impairment in Motor Function
Chronic Microglial Activation in the GFAP-IL6 Mouse Contributes to Age-Dependent Cerebellar Volume Loss and Impairment in Motor Function
复制标题
GFAP-IL 6小鼠中的慢性小胶质细胞活化导致了小脑体积的减少和运动功能的损害
DOI：
10.3389/fnins.2019.00303
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发表时间：
2019-04-03
影响因子：
4.3
通讯作者：
Muench, Gerald
中科院分区：
文献类型：
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作者：
Gyengesi, Erika;Rangel, Alejandra;Muench, Gerald
慢性小胶质细胞活化是许多慢性神经退行性疾病的显著特征，包括帕金森病和阿尔茨海默病。为了研究慢性小胶质细胞活化在整个寿命期间对小脑结构和运动功能的影响，使用转基因GFAP-IL 6小鼠模型。该研究的目的是检查炎症标志物和神经元变性，同时与WT（C57 BL/6）小鼠相比，表征GFAP-IL 6小鼠在3、6、14和24月龄时的运动性能。关于小脑神经炎症的标志物，早在3个月大时就观察到lba 1+小胶质细胞数量增加。此外，在所有时间点，GFAP-IL 6小鼠中的TNF-α水平均显着高于WT小鼠。在生命后期观察到GFAP-IL 6和WT小鼠之间小脑体积的差异，从6个月开始，并且在老年（24个月大）GFAP-IL 6小鼠中增加至约50%的损失。还通过使用突触前（突触体蛋白）和突触后（PSD 95）标记物评估突触缺陷。虽然突触素水平保持不变，但与14个月后的WT同窝出生小鼠相比，老化GFAP-IL 6小鼠中的PSD 95水平降低。为了评估小胶质细胞活化和神经变性对行为的影响，进行了各种运动功能测试、半定量小脑共济失调评分、加速杆、平衡木行走和旷场测试。在许多运动功能测试中观察到基因型之间的年龄依赖性差异。例如，在6个月龄时观察到加速杆性能降低和共济失调评分升高，随后在14个月龄时进行平衡木行走试验显示差异。总之，本研究构成了对GFAP-IL 6小鼠脑中导致运动性能恶化的炎症、突触和神经退行性变化的全面的、年龄依赖性检查。结果还表明，GFAP-IL 6小鼠中的早期慢性小胶质细胞活化导致生命后期可观察到的小脑体积损失和运动缺陷。
Chronic microglial activation is a prominent feature of many chronic neurodegenerative diseases, including Parkinson's and Alzheimer's disease. To investigate the effects of chronic microglial activation on cerebellar structure and motor function throughout the lifespan, the transgenic GFAP-IL6 mouse model was used. The aim of the study was to examine inflammatory markers and neuronal degeneration while simultaneously characterizing the motor performance of GFAP-IL6 mice at 3, 6, 14, and 24 months of age in comparison to WT (C57BL/6) mice. In respect to markers of neuroinflammation in the cerebellum, increased numbers of lba1+ microglia were observed as early as at 3 months of age. In addition, TNF-alpha levels proved to be significantly higher in the GFAP-IL6 compared to WT mice at all time points. A difference in cerebellar volume between the GFAP-IL6 and WT mice was observed later in life, starting at 6 months and increasing to a loss of about 50% in aged (24 months old) GFAP-IL6 mice. Synaptic deficits were also assessed by using pre- (synaptophysin) and post-synaptic (PSD95) markers. While synaptophysin levels remained unchanged, PSD95 levels decreased in the aging GFAP-IL6 mice compared to their WT littermates from 14 months onward. To assess the effect of microglia activation and neurodegeneration on behavior, a variety of motor function tests, semi-quantitative cerebellar ataxia score, accelerod, beam walking, and open field tests were performed. An age-dependent difference between the genotypes was observed in many of the motor function tests. For example, reduced performance on the accelerod and higher ataxia scores were observed at 6 months of age, followed by the beam walking test showing differences at 14 months of age. In summary, this study constitutes a comprehensive, age-dependent examination of inflammatory, synaptic and neurodegenerative changes in the brains of GFAP-IL6 mice leading to a deterioration in motor performance. The results also indicate that early chronic microglia activation in the GFAP-IL6 mouse leads to observable cerebellar volume loss and motor deficits later in life.