The New York Stem Cell Foundation, New York, New York, United States of America.
Department of Pathology & Cell Biology and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, United States of America.
PLoS One. 2014 Jan 8;9(1):e84547. doi: 10.1371/journal.pone.0084547. eCollection 2014.
Presenilin 1 (PSEN1) encodes the catalytic subunit of γ-secretase, and PSEN1 mutations are the most common cause of early onset familial Alzheimer's disease (FAD). In order to elucidate pathways downstream of PSEN1, we characterized neural progenitor cells (NPCs) derived from FAD mutant PSEN1 subjects. Thus, we generated induced pluripotent stem cells (iPSCs) from affected and unaffected individuals from two families carrying PSEN1 mutations. PSEN1 mutant fibroblasts, and NPCs produced greater ratios of Aβ42 to Aβ40 relative to their control counterparts, with the elevated ratio even more apparent in PSEN1 NPCs than in fibroblasts. Molecular profiling identified 14 genes differentially-regulated in PSEN1 NPCs relative to control NPCs. Five of these targets showed differential expression in late onset AD/Intermediate AD pathology brains. Therefore, in our PSEN1 iPSC model, we have reconstituted an essential feature in the molecular pathogenesis of FAD, increased generation of Aβ42/40, and have characterized novel expression changes.
早老素 1（PSEN1）编码 γ-分泌酶的催化亚基，PSEN1 突变是早发性家族性阿尔茨海默病（FAD）最常见的原因。为了阐明 PSEN1 下游的途径，我们对源自 FAD 突变 PSEN1 患者的神经祖细胞（NPC）进行了特征分析。因此，我们从携带 PSEN1 突变的两个家族的受影响和未受影响的个体中生成了诱导多能干细胞（iPSC）。与对照相比，PSEN1 突变体成纤维细胞和 NPC 产生的 Aβ42 与 Aβ40 的比例更高，而 PSEN1 NPC 中的升高比例甚至比成纤维细胞更为明显。分子谱分析确定了 14 个在 PSEN1 NPC 中相对于对照 NPC 差异调节的基因。其中 5 个靶标在晚发性 AD/中间 AD 病理脑中表现出差异表达。因此，在我们的 PSEN1 iPSC 模型中，我们重现了 FAD 分子发病机制中的一个重要特征，即 Aβ42/40 的产生增加，并对新的表达变化进行了特征分析。
