Arendt T, Holzer M, Gärtner U
Paul Flechsig Institute of Brain Research, Department of Neuroanatomy, University of Leipzig, Federal Republic of Germany.
J Neural Transm (Vienna). 1998;105(8-9):949-60. doi: 10.1007/s007020050104.
Neurodegeneration and cell death in Alzheimer's disease might be associated with aberrant proliferative mechanisms and activation of cell-cycle related events. We reported previously on the elevated expression of the cyclin dependent kinase inhibitor p16INK4a in Alzheimer's disease closely associated with neurofibrillary degeneration. In the present study, we demonstrate that other members of the INK4-family of cyclin dependent kinase inhibitors such as p15INK4b, p18INK4c and p19INK4d that bind directly to cdk4/6 or to complexes of cdk4/6 with D-type cyclins are all elevated. In contrast, no indication of altered expression of the cyclin dependent kinase inhibitors p21Cip1 and p27Kip1 were observed. Inhibitors of the INK4-family were strongly expressed in tangle-bearing neurones and neuritic components of plaques. A much lower expression was also seen in astrocytes. These findings add further evidence to the suggestion that a dysfunction of cell cycle regulation is of critical importance in the pathomechanism of Alzheimer's disease.
阿尔茨海默病中的神经退行性变和细胞死亡可能与异常的增殖机制以及细胞周期相关事件的激活有关。我们之前报道过，细胞周期蛋白依赖性激酶抑制剂p16INK4a在阿尔茨海默病中的表达升高，这与神经原纤维变性密切相关。在本研究中，我们证明细胞周期蛋白依赖性激酶抑制剂INK4家族的其他成员，如直接与cdk4/6或cdk4/6与D型细胞周期蛋白的复合物结合的p15INK4b、p18INK4c和p19INK4d，其表达均升高。相比之下，未观察到细胞周期蛋白依赖性激酶抑制剂p21Cip1和p27Kip1表达改变的迹象。INK4家族抑制剂在含有神经缠结的神经元和斑块的神经突成分中强烈表达。在星形胶质细胞中也观察到低得多的表达。这些发现进一步证明了细胞周期调节功能障碍在阿尔茨海默病发病机制中至关重要的观点。
