Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan.
Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan; Research Fellow of Japan Society for the Promotion of Science (JSPS), Tokyo 102-0083, Japan.
Stem Cell Reports. 2023 Sep 12;18(9):1854-1869. doi: 10.1016/j.stemcr.2023.08.002. Epub 2023 Aug 31.
The APOE4 genotype is the strongest risk factor for the pathogenesis of sporadic Alzheimer's disease (AD), but the detailed molecular mechanism of APOE4-mediated synaptic impairment remains to be determined. In this study, we generated a human astrocyte model carrying the APOE3 or APOE4 genotype using human induced pluripotent stem cells (iPSCs) in which isogenic APOE4 iPSCs were genome edited from healthy control APOE3 iPSCs. Next, we demonstrated that the astrocytic APOE4 genotype negatively affects dendritic spine dynamics in a co-culture system with primary neurons. Transcriptome analysis revealed an increase of EDIL3, an extracellular matrix glycoprotein, in human APOE4 astrocytes, which could underlie dendritic spine reduction in neuronal cultures. Accordingly, postmortem AD brains carrying the APOE4 allele have elevated levels of EDIL3 protein deposits within amyloid plaques. Together, these results demonstrate the novel deleterious effect of human APOE4 astrocytes on synaptic architecture and may help to elucidate the mechanism of APOE4-linked AD pathogenesis.
载脂蛋白 E4 基因型是散发性阿尔茨海默病 (AD) 发病机制的最强风险因素，但载脂蛋白 E4 介导的突触损伤的详细分子机制仍有待确定。在这项研究中，我们使用人类诱导多能干细胞 (iPSC) 生成了携带 APOE3 或 APOE4 基因型的人类星形胶质细胞模型，其中同源 APOE4 iPSC 是从健康对照 APOE3 iPSC 中基因组编辑而来的。接下来，我们证明了星形胶质细胞 APOE4 基因型会在与原代神经元共培养的系统中对树突棘动力学产生负面影响。转录组分析显示，人类 APOE4 星形胶质细胞中 EDIL3（一种细胞外基质糖蛋白）增加，这可能是神经元培养物中树突棘减少的基础。相应地，携带 APOE4 等位基因的 AD 尸检大脑在淀粉样斑块内有升高的 EDIL3 蛋白沉积水平。总之，这些结果表明人类 APOE4 星形胶质细胞对突触结构具有新的有害影响，并可能有助于阐明 APOE4 相关 AD 发病机制的机制。
