Masliah E, Mallory M, Alford M, Tanaka S, Hansen L A
Department of Neurosciences, School of Medicine, University of California, San Diego, La Jolla 92093-0624, USA.
J Neuropathol Exp Neurol. 1998 Nov;57(11):1041-52. doi: 10.1097/00005072-199811000-00007.
Recent studies have shown that deficient functioning of glutamate transporters (GTs) in Alzheimer disease (AD) might lead to neurodegeneration via excitotoxicity; however, the characteristics of cell death and pathways involved are not yet clear. The main objective of the present study was to determine if deficient GT functioning in AD could be associated with cell damage and caspase activation. For this purpose, we analyzed the levels of caspase-1 and 3 immunoreactivity in AD and control brains and correlated this data with the numbers of cells displaying DNA fragmentation, GT activity, and amyloid precursor protein (APP) mRNA expression. Compared to controls, AD cases showed extensive positive labeling of neurons and glial cells with an assay for DNA fragmentation suggestive of cell damage, as well as increased neuronal caspase-3 and Bcl-2 immunoreactivity. Linear regression analysis showed a strong negative correlation between GT activity and apoptosis, and between deficient GT functioning and caspase-3 immunoreactivity. Neurons displaying DNA fragmentation presented more intense caspase-3 immunoreactivity than intact neurons. In addition, the altered ratio between the spliced forms of APP correlated with DNA fragmentation and caspase-3 immunolabeling. Taken together, these results support the possibility that excitotoxic injury associated with deficient GT functioning and an imbalance in ratio of spliced APP forms might lead to cell death via caspase-3 activation.
最近的研究表明，阿尔茨海默病（AD）中谷氨酸转运体（GTs）功能缺陷可能通过兴奋性毒性导致神经退行性变；然而，细胞死亡的特征及相关途径尚不清楚。本研究的主要目的是确定AD中GT功能缺陷是否与细胞损伤和半胱天冬酶激活有关。为此，我们分析了AD患者和对照者大脑中半胱天冬酶-1和3的免疫反应性水平，并将这些数据与显示DNA片段化的细胞数量、GT活性以及淀粉样前体蛋白（APP）mRNA表达进行关联。与对照组相比，AD病例中神经元和胶质细胞经DNA片段化检测显示广泛的阳性标记，提示细胞损伤，同时神经元半胱天冬酶-3和Bcl-2免疫反应性增加。线性回归分析显示GT活性与细胞凋亡之间，以及GT功能缺陷与半胱天冬酶-3免疫反应性之间存在强烈的负相关。显示DNA片段化的神经元比完整神经元呈现出更强的半胱天冬酶-3免疫反应性。此外，APP剪接形式之间改变的比例与DNA片段化和半胱天冬酶-3免疫标记相关。综上所述，这些结果支持这样一种可能性，即与GT功能缺陷和剪接APP形式比例失衡相关的兴奋性毒性损伤可能通过半胱天冬酶-3激活导致细胞死亡。
