Department of Neuroscience, Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK.
Neurobiol Aging. 2011 Oct;32(10):1795-807. doi: 10.1016/j.neurobiolaging.2011.04.013. Epub 2011 Jun 25.
Astrocytes contribute to a variety of functions in the brain, including homeostasis, synapse formation, plasticity, and metabolism. Astrocyte dysfunction may disrupt their normal role, including neuronal support, thereby contributing to neurodegenerative pathologies, including Alzheimer's disease (AD). To understand the role of astrocytes in the pathogenesis of age-related disorders, we isolated astrocytes by laser capture microdissection, using glial fibrillary acidic protein (GFAP) as a marker, and characterized the astrocyte transcriptome at different Braak neurofibrillary tangle stages in postmortem temporal cortex samples derived from the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS) cohort, using microarray analysis. The largest number of significant, differentially expressed genes were identified when the expression profile of astrocytes from isocortical stages of neurofibrillary tangle pathology (Braak stages V-VI) were compared with entorhinal stages (Braak stages I-II). Dysregulation of genes associated with the actin cytoskeleton, proliferation, apoptosis, and ubiquitin-mediated proteolysis occurred at low Braak stages, while altered regulation of intracellular signaling pathways, including insulin, phosphatidylinositol 3-kinase (PI3K)/Akt, and mitogen-activated protein kinase (MAPK) pathways were primarily associated with high levels of Alzheimer-type pathology, and occurred at lower Braak stages in individuals with the APOEε4 allele. Our findings implicate astrocyte dysfunction in the pathogenesis of neurodegenerative pathology in the aging brain, and provide a basis for future candidate studies based on specific pathways.
星形胶质细胞在大脑中发挥着多种功能，包括维持内环境稳定、突触形成、可塑性和代谢等。星形胶质细胞功能障碍可能会破坏其正常功能，包括对神经元的支持，从而导致神经退行性病变，包括阿尔茨海默病（AD）。为了了解星形胶质细胞在与年龄相关的疾病发病机制中的作用，我们使用胶质纤维酸性蛋白（GFAP）作为标记物，通过激光捕获显微切割分离星形胶质细胞，使用微阵列分析方法，对来自医学研究委员会认知功能和衰老研究（MRC CFAS）队列的死后颞叶皮质样本中不同 Braak 神经纤维缠结阶段的星形胶质细胞转录组进行了特征分析。当将具有神经纤维缠结病理学（Braak 阶段 V-VI）的大脑皮质中间层星形胶质细胞的表达谱与内嗅皮层阶段（Braak 阶段 I-II）进行比较时，鉴定出数量最多的具有显著差异表达的基因。在低 Braak 阶段，与肌动蛋白细胞骨架、增殖、凋亡和泛素介导的蛋白水解相关的基因失调，而与胰岛素、磷脂酰肌醇 3-激酶（PI3K）/Akt 和丝裂原激活蛋白激酶（MAPK）通路等细胞内信号通路的调节改变主要与高水平的阿尔茨海默病样病理相关，并且在携带 APOEε4 等位基因的个体中，在较低的 Braak 阶段发生。我们的研究结果表明，星形胶质细胞功能障碍与衰老大脑中神经退行性病变的发病机制有关，并为基于特定途径的未来候选研究提供了基础。
