Hua Xiangdong, Lei Ming, Ding Jiong, Han Qunying, Hu Gang, Xiao Ming
Jiangsu Province Key Laboratory of Neurodegeneration, Department of Anatomy, Histology and Pharmacology of Nanjing Medical University, Nanjing, China.
Exp Neurol. 2008 Apr;210(2):709-18. doi: 10.1016/j.expneurol.2008.01.009. Epub 2008 Jan 26.
Astrocytes are implicated in the pathological changes of Alzheimer's disease. Our previous studies have demonstrated that estrogen deprivation and oxidative stress act synergistically to accelerate the progress of Alzheimer's disease. Long-term D-galactose injection combined with ovariectomy may serve as a rodent model for Alzheimer's disease. To address the potential contribution of astroglia to the Alzheimer's disease pathogenesis, we investigated pathological and biochemical alterations of astrocytes under this animal model. Ovariectomized rats injected with D-galactose for 2 weeks showed extensive localization of glial fibrillary acidic protein immunoreactive astrocytes and slightly elevated glutathione levels in the hippocampus without significant impairments in the water maze test and deficits of the cholinergic analyses, compared to the saline-injected rats. Ovariectomized rats injected with D-galactose for 6 weeks, however, exhibited degeneration of astrocytes and decreased glutathione levels in the hippocampus, accompanied with severe dysfunction of behavioral test and deficiency of cholinergic terminals. Electron microscopy further confirmed the pathological changes of astrocytes, especially in the aggregated area of synapse and brain microvessels. Consistent with degeneration of perivascular astrocytic endfeet, analysis of the horseradish peroxidase demonstrated an impairment of the blood-brain barrier permeability. These findings indicate that biochemical and pathological alterations of astrocytes may partially contribute to exacerbating neuronal deficits in the course of Alzheimer's disease. Restoring neuroprotective potential of astrocytes may be a useful therapeutic target for Alzheimer's disease and other neurodegenerative diseases.
星形胶质细胞与阿尔茨海默病的病理变化有关。我们之前的研究表明，雌激素缺乏和氧化应激协同作用，加速阿尔茨海默病的进展。长期注射D-半乳糖并结合卵巢切除术可作为阿尔茨海默病的啮齿动物模型。为了探讨星形胶质细胞对阿尔茨海默病发病机制的潜在作用，我们在该动物模型下研究了星形胶质细胞的病理和生化改变。与注射生理盐水的大鼠相比，注射D-半乳糖2周的去卵巢大鼠海马中胶质纤维酸性蛋白免疫反应性星形胶质细胞广泛定位，谷胱甘肽水平略有升高，在水迷宫试验中无明显损伤，胆碱能分析无缺陷。然而，注射D-半乳糖6周的去卵巢大鼠表现出星形胶质细胞退化，海马中谷胱甘肽水平降低，同时伴有行为测试严重功能障碍和胆碱能终末缺陷。电子显微镜进一步证实了星形胶质细胞的病理变化，尤其是在突触和脑微血管的聚集区域。与血管周围星形胶质细胞终足的退化一致，辣根过氧化物酶分析表明血脑屏障通透性受损。这些发现表明，星形胶质细胞的生化和病理改变可能部分导致阿尔茨海默病病程中神经元缺陷的加剧。恢复星形胶质细胞的神经保护潜能可能是治疗阿尔茨海默病和其他神经退行性疾病的有效靶点。
