Gene expression data from temporal cortex of young adult, old and AD-like Microcebus murinus

Aging is the primary risk factor of neurodegenerative disorders such as Alzheimer's disease (AD). However, the molecular events occurring during brain aging are extremely complex and still largely unknown. For a better understanding of these age-associated modifications, animal models as close as possible to humans are needed. We thus analyzed the transcriptome of the temporal cortex of the primate Microcebus murinus using human oligonucleotide microarrays (Affymetrix). Gene expression profiles were assessed in the temporal cortex of 6 young adults, 10 healthy old animals and 2 old, "AD-like" animals that presented b-amyloid plaques and cortical atrophy, which are pathognomonic signs of AD in humans. Gene expression data of the 14,911 genes that were detected in at least 3 samples were analyzed. By SAM (significance analysis of microarrays), we identified 47 genes that discriminated young from healthy old and "AD-like" animals. These findings were confirmed by principal component analysis (PCA). ANOVA of the expression data from the three groups identified 695 genes (including the 47 genes previously identified by SAM and PCA) with significant changes of expression in old and "AD-like" in comparison to young animals. About one third of these genes showed similar changes of expression in healthy aging and in “AD-like” animals, whereas more than two thirds showed opposite changes in these two groups in comparison to young animals. Hierarchical clustering analysis of the 695 markers indicated that each group had distinct expression profiles which characterized each group, especially the "AD-like" group. Functional categorization showed that most of the genes that were up-regulated in healthy old and down-regulated in "AD-like" animals belonged to metabolic pathways, particularly protein synthesis. These data suggest the existence of compensatory mechanisms during physiological brain aging that disappear in “AD-like” animals. These results open the way to new exploration of physiological and “AD-like” aging in primates. Microcebus murinus were divided in 3 groups: the first group included 6 young adults (4 females and 2 males), the second included 10 healthy old animals (7 females and 3 males) and the third one was composed by 2 "AD-like" old females. Since Microcebus murinus microarrays do not exist, we decided to use Affymetrix human genome chips (HG U133 plus 2), since studies have illustrated the feasibility of detecting non-human primate brain transcripts using human genome chips.

衰老是阿尔茨海默病（Alzheimer's disease, AD）等神经退行性疾病的首要风险因素。然而，大脑衰老过程中发生的分子事件极为复杂，目前仍未得到充分解析。为更好地理解这类与年龄相关的脑内变化，亟需使用尽可能贴近人类的动物模型。因此，本研究采用人类寡核苷酸微阵列（Affymetrix），对非人灵长类动物倭狐猴（Microcebus murinus）的颞皮层转录组进行了分析。我们对6只年轻成年个体、10只健康老年个体，以及2个表现出β-淀粉样斑块与皮层萎缩（人类阿尔茨海默病的病理性特征征象）的“类AD”老年个体的颞皮层基因表达谱进行了检测。对至少在3个样本中被检出的14911个基因的表达数据展开了分析。通过微阵列显著性分析（Significance Analysis of Microarrays, SAM），我们鉴定出47个可区分年轻个体与健康老年、“类AD”个体的基因。主成分分析（Principal Component Analysis, PCA）验证了这一结果。对三组样本的表达数据进行方差分析（Analysis of Variance, ANOVA）后，共鉴定出695个基因（包含此前通过SAM与PCA鉴定出的47个基因）：相较于年轻个体，这些基因在老年及“类AD”个体中存在显著表达差异。其中约三分之一的基因在健康衰老与“类AD”个体中呈现相似的表达变化趋势，而超过三分之二的基因在这两组与年轻个体的对比中呈现相反的表达变化。对这695个标记基因进行层级聚类分析的结果显示，三组样本均拥有各自独特的表达谱，可用于区分各组，尤以“类AD”组的区分效果最为显著。功能分类结果表明，在健康老年个体中上调、而在“类AD”个体中下调的多数基因，隶属于代谢通路，尤其是蛋白质合成相关通路。上述数据提示，生理性脑衰老过程中存在代偿机制，而这类机制在“类AD”个体中不复存在。本研究结果为探索灵长类动物的生理性衰老与“类AD”衰老开辟了全新的研究方向。倭狐猴（Microcebus murinus）被划分为三组：第一组包含6只年轻成年个体（4雌2雄），第二组为10只健康老年个体（7雌3雄），第三组由2只“类AD”老年雌性个体组成。由于目前尚无倭狐猴专用的微阵列芯片，我们选用了Affymetrix人类基因组芯片（HG U133 plus 2），已有研究证实利用人类基因组芯片检测非人灵长类脑转录本的可行性。