中文摘要：

目的探讨阿尔茨海默病（AD）病变与肝Ⅰ相药酶基因表达的相关性,为早期和长期药物干预AD病程提供实验参考。方法制备B6.129-PS1M146V/APPSwe/Tau P301L三重转基因AD模型小鼠（3×Tg AD小鼠）及同系非转基因正常小鼠（NTg小鼠）肝组织总RNA和总蛋白质样品,逆转录PCR/实时荧光定量PCR技术检测肝核因子4（HNF4）等7种核受体和细胞色素氧化酶P4501a2（Cyp1a2）等7种CYP基因mRNA相对表达量,比较基因转录谱差异;Western蛋白印迹法检测技术检测差异显著的目的基因蛋白质水平。结果与NTg小鼠相比,3×Tg AD小鼠HNF4、雌激素受体（ERα）及组成型雄甾烷受体均下调近66%（P〈0.01）,孕烷X受体和芳香烃受体分别上调1.84和1.64倍（P〈0.05）,糖皮质激素受体及受氧化应激激活的核因子E2相关因子未见显著变化;主要药物代谢酶Cyp2b10及Cyp2a5 mRNA分别降低至正常小鼠水平的3%（即下降97%,P〈0.01）和30%（P〈0.05）,Cyp2e1、Cyp2j9、Cyp3a11基因的转录水平则分别上调了2.26倍、2.42倍和3.66倍（P〈0.05）;Cyp1a2和Cyp2d22基因转录在两种小鼠中无明显差异。Western蛋白印迹分析证实,3×Tg AD小鼠ERα和CYP2a5明显下降（P〈0.05）而Cyp3a11表达则明显上升（P〈0.05）,蛋白质表达变化的趋势与其相应mRNA水平改变一致。结论 3×Tg AD小鼠肝内核受体基因及CYP酶基因转录谱发生显著改变,提示AD病变可能干扰机体肝代谢功能,对机体内源性及外源性化合物生物转运产生影响。

英文摘要：

OBJECTIVE To investigate the relationship between hepatic P450 expression changes and Alzheimer disease（ AD） pathogenesis,and provide potential biomarkers for early on-set AD diagnosis and / or therapeutic targets for long-term drug intervention of AD. METHODS The RNA and protein samples of 3 × Tg AD mice and NTg mice were prepared. A comparative analysis using RT-PCR / QPCR was conducted to validate relative mRNA levels of seven nuclear receptors and seven cytochrome P450 genes in NTg and 3 × Tg AD model mice. Western blot was performed to confirm the protein expression changes of genes with distinct difference between NTg and 3 × Tg AD mice. RESULTS Compared with the NTg mice,3 × Tg AD mice hepatic nuclear factor 4（ HNF4）,estrogen receptor（ ERα） and constitutive androstane receptor（ CAR） mRNA decreased nearly by 66 percent（ P 0. 01）. While pregnane Xreceptor（ PXR） and aryl hydrocarbon receptor（ AhR） increased by 184% and 164% respectively（ P 0. 05）. Glucocortical receptor（ GR） and nuclear factor erythroid 2 related factor（ Nrf2） showed no significant changes. mRNA Levels of Cyp2b10 and Cyp2a5 dropped to 3%（ ~ 33-times lower,P 0. 01）and 30%（ P 0. 05） of that in 3 × Tg AD mice,respectively. In contrast,Cyp2e1,Cyp2j9 and Cyp3a11 mRNA increased by 226%,242% and 366%（ P 0. 05） respectively. There was no ovbvious different in Cyp1a2 and Cyp2d22 transcription between the two groups of animals. Western blot analysis confirmed that protein levels of ERα and Cyp2a5 in 3 × Tg AD mice significantly decreased（ P 0. 01 or P 0. 05） while CYP3a11 expression significantly increased（ P 0. 05）. These protein expression changes were consistent with the mRNA profile changes observed in QPCR analysis. CONCLUSION The liver nuclear receptor gene expressions and hepatic P450 enzymes expression profiles of 3 × Tg AD mice have been significantly altered,suggesting that AD pathogenesis may interfere with the body＇s metabolism of liver function while affecting biologica