Molecular signatures in post-mortem brain tissue of younger individuals at high risk for Alzheimer's disease as based on APOE genotype.
Molecular signatures in post-mortem brain tissue of younger individuals at high risk for Alzheimer's disease as based on APOE genotype.
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DOI：
10.1038/mp.2010.57
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发表时间：
2011-08
影响因子：
11
通讯作者：
Goldberg TE
中科院分区：
文献类型：
--
作者：
Conejero-Goldberg C;Hyde TM;Chen S;Dreses-Werringloer U;Herman MM;Kleinman JE;Davies P;Goldberg TE
阿尔茨海默病(AD)是一种神经退行性疾病，在组织病理学上以神经炎性斑块和神经纤维缠结为特征。这项转录图谱研究的目的是在分子水平上识别神经易感性和内在神经保护因素，而不是被病理的下游后果混淆。因此，我们研究了28例非APOE4携带者(称为APOE3组)和13例APOE4携带者的死后皮质组织。由于APOE基因是晚发性AD的主要遗传危险因素，前者发病风险较低，而后者发病风险较高。死亡时的平均年龄为42岁，死亡时没有脑组织病理学诊断为阿尔茨海默病。我们首先得出了相对不受AD影响的区域(初级躯体感觉皮质，BA 1/2/3)和已知易受AD病理影响的区域(颞中回，BA 21)的皮质组织之间的表达差异分数。然后，我们在APOE3(低风险)和APOE4(高危)基因型组的组间比较中对比了这些地区间差异的幅度。我们确定了70个在不同组之间存在显著差异的转录。这些基因包括EGFR、CNTFR、CASP6、GRIA2、CTNNB1、FKBPL、LGALS1和PSMC5。使用实时定量聚合酶链式反应，我们验证了这些发现。此外，我们还发现APOE本身的表达存在地区差异。我们还发现在APOE4组中有多个京都通路被破坏，包括那些涉及线粒体功能、钙调节和细胞周期重入的通路。为了确定我们转录发现的功能意义，我们使用生物信息学途径分析来证明上面列出的分子组成了一个相互连接的网络，APOE，APP和MAPT。总体而言，我们的结果表明，我们在单个转录本和信号通路中观察到的异常不是诊断斑块和缠绕病理的后果，而是在它之前，因此可能是导致临床AD的长分子前驱症状的原因联系。
Alzheimer’s disease (AD) is a neurodegenerative condition characterized histopathologically by neuritic plaques and neurofibrillary tangles. The objective of this transcriptional profiling study was to identify both neurosusceptibility and intrinsic neuroprotective factors at the molecular level, not confounded by the downstream consequences of pathology. We thus studied post-mortem cortical tissue in 28 cases that were non-APOE4 carriers (called the APOE3 group) and 13 cases that were APOE4 carriers. As APOE genotype is the major genetic risk factor for late-onset AD, the former group was at low risk for development of the disease and the latter group was at high risk for the disease. Mean age at death was 42 years and none of the brains had histopathology diagnostic of AD at the time of death. We first derived interregional difference scores in expression between cortical tissue from a region relatively invulnerable to AD (primary somatosensory cortex, BA 1/2/3) and an area known to be susceptible to AD pathology (middle temporal gyrus, BA 21). We then contrasted the magnitude of these interregional differences in between-group comparisons of the APOE3 (low risk) and APOE4 (high risk) genotype groups. We identified 70 transcripts that differed significantly between the groups. These included EGFR, CNTFR, CASP6, GRIA2, CTNNB1, FKBPL, LGALS1 and PSMC5. Using real-time quantitative PCR, we validated these findings. In addition, we found regional differences in the expression of APOE itself. We also identified multiple Kyoto pathways that were disrupted in the APOE4 group, including those involved in mitochondrial function, calcium regulation and cell-cycle reentry. To determine the functional significance of our transcriptional findings, we used bioinformatics pathway analyses to demonstrate that the molecules listed above comprised a network of connections with each other, APOE, and APP and MAPT. Overall, our results indicated that the abnormalities that we observed in single transcripts and in signaling pathways were not the consequences of diagnostic plaque and tangle pathology, but preceded it and thus may be a causative link in the long molecular prodrome that results in clinical AD.
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DOI：
10.1038/npp.2008.172
发表时间：
2009-01
期刊：
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
影响因子：
--
作者：
通讯作者：
--
影响因子：
2.9
作者：
Cecarini, Valentina;Bonfili, Laura;Eleuteri, Anna Maria
通讯作者：
Eleuteri, Anna Maria
影响因子：
16.2
作者：
Hoeffer, Charles A.;Tang, Wei;Klann, Eric
通讯作者：
Klann, Eric
影响因子：
3.7
作者：
Arnold, Steven E.;Hyman, Bradley T.;Van Hoesen, Gary W.
通讯作者：
Van Hoesen, Gary W.
影响因子：
14.9
作者：
Barnes M;Freudenberg J;Thompson S;Aronow B;Pavlidis P
通讯作者：
Pavlidis P