PDF(Pubmed)
Abstract：
Late-onset Alzheimer\'s disease (AD) is a complex multifactorial disease. The greatest known risk factor for late-onset AD is the E4 allele of the apolipoprotein E (APOE), while increasing age is the greatest known non-genetic risk factor. The cell type-specific functions of neural stem cells (NSCs), in particular their stem cell plasticity, remain poorly explored in the context of AD pathology. Here, we describe a new model that employs late-onset AD patient-derived induced pluripotent stem cells (iPSCs) to generate NSCs and to examine the role played by APOE4 in the expression of aging markers such as sirtuin 1 (SIRT1) in comparison to healthy subjects carrying APOE3. The effect of aging was investigated by using iPSC-derived NSCs from old age subjects as healthy matched controls. Transcript and protein analysis revealed that genes were expressed differently in NSCs from late-onset AD patients, e.g., exhibiting reduced autophagy-related protein 7 (ATG7), phosphatase and tensin homolog (PTEN), and fibroblast growth factor 2 (FGF2). Since SIRT1 expression differed between APOE3 and APOE4 NSCs, the suppression of APOE function in NSCs also repressed the expression of SIRT1. However, the forced expression of APOE3 by plasmids did not recover differently expressed genes. The altered aging markers indicate decreased plasticity of NSCs. Our study provides a suitable in vitro model to investigate changes in human NSCs associated with aging, APOE4, and late-onset AD.
摘要：
迟发性阿尔茨海默病(AD)是一种复杂的多因素疾病。已知晚发性AD的最大危险因素是载脂蛋白E（APOE）的E4等位基因，而年龄增长是已知的最大的非遗传危险因素。神经干细胞（NSC）的细胞类型特异性功能，特别是它们的干细胞可塑性，在AD病理学的背景下仍然缺乏探索。这里,我们描述了一种新的模型,该模型采用源自晚发性AD患者的诱导多能干细胞(iPSCs)来产生神经干细胞,并与携带APOE3的健康受试者相比,研究了APOE4在衰老标志物如sirtuin1(SIRT1)表达中的作用.通过使用来自老年受试者的iPSC衍生的NSC作为健康匹配的对照来研究衰老的影响。转录和蛋白质分析显示，基因在迟发性AD患者的神经干细胞中表达不同，例如，表现出减少的自噬相关蛋白7（ATG7），磷酸酶和张力蛋白同源物（PTEN），和成纤维细胞生长因子2(FGF2)。由于SIRT1表达在APOE3和APOE4NSC之间不同，NSC中APOE功能的抑制也抑制SIRT1的表达。然而,质粒强制表达APOE3并没有恢复不同表达的基因。改变的老化标志物表明NSC的可塑性降低。我们的研究提供了一个合适的体外模型来研究与衰老相关的人类神经干细胞的变化。APOE4和晚发性AD。
