Distinct chronology of neuronal cell cycle re-entry and tau pathology in the 3xTg-AD mouse model and Alzheimer's disease patients.
Distinct chronology of neuronal cell cycle re-entry and tau pathology in the 3xTg-AD mouse model and Alzheimer's disease patients.
复制标题
DOI：
10.3233/jad-141083
复制
发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Lee HG
中科院分区：
文献类型：
--
作者：
Hradek AC;Lee HP;Siedlak SL;Torres SL;Jung W;Han AH;Lee HG
阿尔茨海默病（Alzheimer's disease，AD）的细胞周期重入是AD发生发展的重要病理机制。这种细胞周期相关蛋白的出现与AD中的tau病理学有关，但两者之间的因果关系和时间关系尚不完全清楚。在这项研究中，我们发现过度磷酸化的视网膜母细胞瘤蛋白（ppRb）是G1/S转换的关键调节因子，与tau过度磷酸化的晚期标志物相关，但与3×Tg-AD小鼠模型中tau改变的其他早期标志物无关。然而，在AD脑中，ppRb可以与tau改变的早期和晚期标志物共定位，并且通常可以在许多变性神经元中单独发现，表明3×Tg-AD小鼠模型和人类AD患者之间的病理学发展不同。这项研究的结论是双重的。首先，我们的发现清楚地证明了异常细胞周期重新进入和tau病理学之间的病理联系。其次，与AD患者相比，3×Tg-AD小鼠中具有tau病理的细胞周期再进入的时间模式不同，表明动物AD模型和人类AD患者之间存在不同的致病机制。
Cell cycle re-entry in Alzheimer’s disease (AD) has emerged as an important pathological mechanism in the progression of the disease. This appearance of cell cycle related proteins has been linked to tau pathology in AD, but the causal and temporal relationship between the two is not completely clear. In this study, we found that hyperphosphorylated retinoblastoma protein (ppRb), a key regulator for G1/S transition, is correlated with a late marker for hyperphosphorylation of tau but not with other early markers for tau alteration in the 3×Tg-AD mouse model. However, in AD brains, ppRb can colocalize with both early and later markers for tau alterations, and can often be found singly in many degenerating neurons, indicating the distinct development of pathology between the 3×Tg-AD mouse model and human AD patients. The conclusions of this study are two-fold. First, our findings clearly demonstrate the pathological link between the aberrant cell cycle re-entry and tau pathology. Second, the chronological pattern of cell cycle re-entry with tau pathology in the 3×Tg-AD mouse is different compared to AD patients suggesting the distinct pathogenic mechanism between the animal AD model and human AD patients.