Ding X L, Husseman J, Tomashevski A, Nochlin D, Jin L W, Vincent I
Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, USA.
Am J Pathol. 2000 Dec;157(6):1983-90. doi: 10.1016/S0002-9440(10)64837-7.
The Cdc25 phosphatases play key roles in cell-cycle progression by activating cyclin-dependent kinases. The latter are absent from neurons that are terminally differentiated in adult brain. However, accumulation of mitotic phosphoepitopes, and re-expression and activation of the M phase regulator, Cdc2/cyclin B, have been described in neurons undergoing degeneration in Alzheimer's disease (AD). To explain this atypical mitotic activation in neurons we investigated the Cdc2-activating Cdc25A phosphatase in human brain. The structural hallmarks of AD neurodegeneration, neurofibrillary tangles and neuritic plaques, were prominently immunolabeled with Cdc25A antibodies. In addition numerous neurons without visible structural alterations were also intensely stained, whereas control brain was very weakly positive. After immunoprecipitation from control and AD tissue, we found that the tyrosine dephosphorylating activity of Cdc25A against exogenous Cdc2 substrate was elevated in AD. Accordingly, Cdc25A from AD tissue displayed increased immunoreactivity with the mitotic phosphoepitope-specific antibody, MPM-2, and co-localized with MPM-2 immunoreactivity in AD neurons. These data suggest that Cdc25A participates in mitotic activation during neurodegeneration. The involvement of Cdc25A in cellular transformation, modulation of the DNA damage checkpoint, and linkage of mitogenic signaling to cell cycle machinery, also implicates one of these cell-cycle pathways in AD pathogenesis.
Cdc25磷酸酶通过激活细胞周期蛋白依赖性激酶在细胞周期进程中发挥关键作用。在成年大脑中终末分化的神经元中不存在后者。然而，在阿尔茨海默病（AD）中发生变性的神经元中，已观察到有丝分裂磷酸表位的积累以及M期调节因子Cdc2/细胞周期蛋白B的重新表达和激活。为了解释神经元中的这种非典型有丝分裂激活，我们研究了人脑中激活Cdc2的Cdc25A磷酸酶。AD神经退行性变的结构特征，即神经原纤维缠结和神经炎性斑块，被Cdc25A抗体显著免疫标记。此外，许多没有明显结构改变的神经元也被强烈染色，而对照脑则呈非常微弱的阳性。从对照组织和AD组织中进行免疫沉淀后，我们发现AD中Cdc25A对外源Cdc2底物的酪氨酸去磷酸化活性升高。相应地，AD组织中的Cdc25A与有丝分裂磷酸表位特异性抗体MPM-2的免疫反应性增加，并在AD神经元中与MPM-2免疫反应性共定位。这些数据表明Cdc25A参与神经退行性变过程中的有丝分裂激活。Cdc25A参与细胞转化、DNA损伤检查点的调节以及有丝分裂信号与细胞周期机制的联系，这也暗示了这些细胞周期途径之一参与了AD的发病机制。
