Neuronal cell cycle re-entry mediates Alzheimer disease-type changes
Neuronal cell cycle re-entry mediates Alzheimer disease-type changes
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DOI：
10.1016/j.bbadis.2006.09.010
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发表时间：
2007-04-01
影响因子：
6.2
通讯作者：
Smith, Mark A.
中科院分区：
文献类型：
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作者：
McShea, Andrew;Lee, Hyoung-gon;Smith, Mark A.
有证据表明，在阿尔茨海默病中，细胞周期相关蛋白在特定的脆弱神经元群体中异位重新表达，这让我们提出了这样的假设，即神经退行性变和癌症一样，是一种细胞周期控制不当的疾病。为了验证这一观点，我们使用腺病毒介导的c-myc和ras癌基因的表达来驱动有丝分裂后的初级皮质神经元进入细胞周期。用BrdU和DAPI测定，神经元细胞周期的重新进入与DNA含量的增加以及细胞周期G(2)/M期的标志物细胞周期蛋白B1的重新表达有关。重要的是，我们还发现原代神经元的细胞周期重新进入导致tau磷酸化和构象变化，类似于阿尔茨海默病。这项研究证实，细胞周期可以在正常静止的神经细胞中被激发，并导致一种与阿尔茨海默病退行性神经元相似的表型。因此，我们的神经细胞模型对于开发新的治疗策略可能非常有价值。(C)2006爱思唯尔B.V.保留所有权利。
Evidence showing the ectopic re-expression of cell cycle-related proteins in specific vulnerable neuronal populations in Alzheimer disease led us to formulate the hypothesis that neurodegeneration, like cancer, is a disease of inappropriate cell cycle control. To test this notion, we used adenoviral-mediated expression of c-myc and ras oncogenes to drive postmitotic primary cortical neurons into the cell cycle. Cell cycle re-entry in neurons was associated with increased DNA content, as determined using BrdU and DAPI, and the re-expression of cyclin B1, a marker for the G(2)/M phase of the cell cycle. Importantly, we also found that cell cycle re-entry in primary neurons leads to tau phosphorylation and conformational changes similar to that seen in Alzheimer disease. This study establishes that the cell cycle can be instigated in normally quiescent neuronal cells and results in a phenotype that shares features of degenerative neurons in Alzheimer disease. As such, our neuronal cell model may be extremely valuable for the development of novel therapeutic strategies. (c) 2006 Elsevier B.V. All rights reserved.