Altered cell cycle-related gene expression in brain and lymphocytes from a transgenic mouse model of Alzheimer's disease [amyloid precursor protein/presenilin 1 (PS1)]
Altered cell cycle-related gene expression in brain and lymphocytes from a transgenic mouse model of Alzheimer's disease [amyloid precursor protein/presenilin 1 (PS1)]
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DOI：
10.1111/j.1460-9568.2012.08178.x
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发表时间：
2012-09-01
影响因子：
3.4
通讯作者：
Martin-Requero, Angeles
中科院分区：
文献类型：
--
作者：
Esteras, Noemi;Bartolome, Fernando;Martin-Requero, Angeles
越来越多的证据表明，许多细胞周期相关蛋白的异常再表达和不适当的神经元细胞周期控制是阿尔茨海默病（AD）发病机制中的关键事件。在AD的鼠模型中也观察到有丝分裂后神经元中细胞周期活化的证据，尽管这些小鼠中的大多数没有显示出神经元体的大量损失。细胞周期的功能障碍似乎影响神经元以外的细胞，因为外周细胞，如AD患者的淋巴细胞和成纤维细胞，显示出对促有丝分裂刺激的反应改变。我们试图确定细胞周期紊乱是否同时存在于淀粉样前体蛋白（APP）/早老素1（PS1）AD小鼠模型的脑细胞和外周细胞中，以验证患者外周细胞的使用，不仅研究细胞周期异常作为AD的致病特征，而且作为测试新治疗方法的手段。通过使用细胞周期途径特异性RT2ProfilerTM PCR阵列，我们检测了APP/PS1小鼠脑和淋巴细胞中许多细胞周期相关基因的变化。此外，我们发现增强的5'-溴-2'-脱氧尿苷掺入到APP/PS1小鼠的淋巴细胞中的DNA中，并增加细胞增殖标记物增殖细胞核抗原（PCNA）和细胞周期蛋白依赖性激酶（CDK）抑制剂Cdkn2a的表达，如在APP/PS1小鼠的皮质神经元中通过免疫组织化学检测到的。两者合计，细胞周期相关的变化，脑和血细胞在这里报告支持有丝分裂失败的假设，在AD和验证使用外周细胞作为替代组织研究AD发病机制的分子基础。
Cumulative evidence indicates that aberrant re-expression of many cell cycle-related proteins and inappropriate neuronal cell cycle control are critical events in Alzheimers disease (AD) pathogenesis. Evidence of cell cycle activation in post-mitotic neurons has also been observed in murine models of AD, despite the fact that most of these mice do not show massive loss of neuronal bodies. Dysfunction of the cell cycle appears to affect cells other than neurons, as peripheral cells, such as lymphocytes and fibroblasts from patients with AD, show an altered response to mitogenic stimulation. We sought to determine whether cell cycle disturbances are present simultaneously in both brain and peripheral cells from the amyloid precursor protein (APP)/presenilin 1 (PS1) mouse model of AD, in order to validate the use of peripheral cells from patients not only to study cell cycle abnormalities as a pathogenic feature of AD, but also as a means to test novel therapeutic approaches. By using cell cycle pathway-specific RT2Profiler (TM) PCR Arrays, we detected changes in a number of cell cycle-related genes in brain as well as in lymphocytes from APP/PS1 mice. Moreover, we found enhanced 5'-bromo-2'-deoxyuridine incorporation into DNA in lymphocytes from APP/PS1 mice, and increased expression of the cell proliferation marker proliferating cell nuclear antigen (PCNA), and the cyclin-dependent kinase (CDK) inhibitor Cdkn2a, as detected by immunohistochemistry in cortical neurons of the APP/PS1 mice. Taken together, the cell cycle-related changes in brain and blood cells reported here support the mitosis failure hypothesis in AD and validate the use of peripheral cells as surrogate tissue to study the molecular basis of AD pathogenesis.