High sensitivity to carcinogens in the brain of a mouse model of Alzheimer's disease
High sensitivity to carcinogens in the brain of a mouse model of Alzheimer's disease
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DOI：
10.1038/onc.2009.503
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发表时间：
2010-04
期刊：
影响因子：
8
通讯作者：
J. Serrano;A. Fernández;R. Martínez-Murillo;Alfredo Martínez
中科院分区：
文献类型：
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作者：
J. Serrano;A. Fernández;R. Martínez-Murillo;Alfredo Martínez
癌症和阿尔茨海默病（AD）在老年患者中很常见。慢性炎症是这两种疾病的特征。 β淀粉样肽是AD炎症的主要诱导剂。此外，慢性炎症会促进癌症，这表明AD患者可能比非痴呆症患者更容易患癌症。为了检验这一假设，我们将致癌物 20-甲基胆蒽注射到过度表达淀粉样前体蛋白 (APP) 和早老素 1 (PS1) 突变形式的转基因小鼠及其野生型 (WT) 小鼠的大脑中，作为 AD 模型。与野生型小鼠相比，突变小鼠产生肿瘤的速度更快，发病率也更高。在未接触致癌物的 3 个月和 12 个月龄的 AD 和 WT 小鼠中测量炎症标志物白细胞介素 (IL)-1α、IL-1β、IL-6、IP-10 和肿瘤坏死因子-α (TNF-α) 的表达。这些细胞因子在老年 AD 小鼠中升高，表明这些动物中存在高度炎症环境。我们还发现老年 AD 小鼠中 p53 突变形式的表达升高，这表明 AD 大脑易发生脑肿瘤的另一种机制。需要报告 AD 和脑癌共病的临床研究来了解我们的观察结果是否适用于人类。
Cancer and Alzheimer's disease (AD) are commonly found among elderly patients. Chronic inflammation is the characteristic of both diseases. Amyloid-β peptide is the main inducer of inflammation in AD. Moreover, chronic inflammation promotes cancer, suggesting that AD patients may be more prone to develop cancer than non-demented people. To test this hypothesis, we injected the carcinogen 20-methylcholanthrene in the brain of transgenic mice overexpressing the mutant forms of amyloid precursor protein (APP) and presenilin 1 (PS1), as a model of AD, and their wild-type (WT) littermates. Mutant mice developed tumors faster and with higher incidence than their WT counterparts. Expression of the inflammatory markers interleukin (IL)-1α, IL-1β, IL-6, IP-10 and tumor necrosis factor-α (TNF-α) was measured in AD and WT mice of 3 and 12 months of age that had not been exposed to the carcinogen. These cytokines were elevated in older AD mice, indicating the existence of a highly inflammatory milieu in these animals. We also found elevated expression of a mutated form of p53 in older AD mice, suggesting an alternative mechanism for the predisposition of AD brains to develop brain tumors. Clinical studies reporting comorbidity of AD and brain cancer are needed to understand whether our observations hold true for humans.