Pike C J, Cummings B J, Cotman C W
Department of Psychobiology, University of California, Irvine 92717-4550, USA.
Exp Neurol. 1995 Apr;132(2):172-9. doi: 10.1016/0014-4886(95)90022-5.
The fibrillar beta-amyloid protein (A beta) plaques of Alzheimer's disease (AD) are associated with reactive astrocytes and dystrophic neurites and have been suggested to contribute to neurodegenerative events in the disease. We recently reported parallel in vitro and in situ findings, suggesting that the adoption of a reactive phenotype and the colocalization of astrocytes with plaques in AD may be mediated in large part by aggregated A beta. Thus, A beta-mediated effects on astrocytes may directly affect disease progression by modifying the degenerative plaque environment. Alternatively, plaque-associated reactive astrocytosis may primarily represent a glial response to the neural injury associated with plaques and not significantly contribute to AD pathology. To investigate the validity of these two positions, we examined the differential colocalization of reactive astrocytes and dystrophic neurites with plaques. Hippocampal sections from AD brains--ranging in neuropathology from mild to severe--were triple-labeled with antibodies recognizing A beta protein, reactive astrocytes, and dystrophic neurites. We observed not only plaques containing both or neither cell type, but also plaques containing (1) reactive astrocytes but not dystrophic neurites and (2) dystrophic neurites but not reactive astrocytes. The relative proportion of plaques colocalized with reactive astrocytes in the absence of dystrophic neurites is relatively high in mild AD but significantly decreases over the course of the disease, suggesting that plaque-associated astrocytosis may be an early and perhaps contributory event in AD pathology rather than merely a response to neuronal injury. These data underscore the potentially significant contributions of reactive astrocytosis in modifying the plaque environment in particular and disease progression in general.
阿尔茨海默病（AD）的纤维状β-淀粉样蛋白（Aβ）斑块与反应性星形胶质细胞和营养不良性神经突相关，并且有人提出它们会导致该疾病中的神经退行性病变。我们最近报告了平行的体外和原位研究结果，表明AD中反应性表型的形成以及星形胶质细胞与斑块的共定位在很大程度上可能由聚集的Aβ介导。因此，Aβ对星形胶质细胞的作用可能通过改变退化的斑块环境直接影响疾病进展。或者，斑块相关的反应性星形胶质细胞增生可能主要代表胶质细胞对与斑块相关的神经损伤的反应，而对AD病理学没有显著贡献。为了研究这两种观点的正确性，我们检查了反应性星形胶质细胞和营养不良性神经突与斑块的差异共定位情况。对来自AD患者大脑的海马切片（神经病理学程度从轻度到重度）用识别Aβ蛋白、反应性星形胶质细胞和营养不良性神经突的抗体进行三重标记。我们不仅观察到含有两种细胞类型或都不含有这两种细胞类型的斑块，还观察到含有（1）反应性星形胶质细胞但不含有营养不良性神经突的斑块以及（2）营养不良性神经突但不含有反应性星形胶质细胞的斑块。在轻度AD中，与反应性星形胶质细胞共定位但不伴有营养不良性神经突的斑块的相对比例较高，但在疾病过程中显著下降，这表明斑块相关的星形胶质细胞增生可能是AD病理学中的一个早期且可能起作用的事件，而不仅仅是对神经元损伤的反应。这些数据强调了反应性星形胶质细胞增生在特别是改变斑块环境以及总体上在疾病进展中可能具有的重大贡献。
