Genetic variants in the apolipoprotein E (APOE) gene affect the onset and progression of Alzheimer's disease (AD). The APOE Christchurch (APOE Ch) variant has been identified as the most prominent candidate for preventing the onset and progression of AD. In this study, we generated isogenic APOE3Ch/3Ch human-induced pluripotent stem cells (iPSCs) from APOE3/3 healthy control female iPSCs and induced them into astrocytes. RNA expression analysis revealed the inherent resilience of APOE3Ch/3Ch astrocytes to induce a reactive state in response to inflammatory cytokines. Moreover, cytokine treatment changed astrocytic morphology with more complexity in APOE3/3 astrocytes, but not in APOE3Ch/3Ch astrocytes, indicating resilience of the rare variant to a reactive state. Interestingly, we observed robust morphological alterations containing more intricate processes when cocultured with iPSC-derived cortical neurons, in which APOE3Ch/3Ch astrocytes reduced complexity compared with APOE3/3 astrocytes. To assess the impacts of tau propagation effects, we next developed a sophisticated and sensitive assay utilizing cortical neurons derived from human iPSCs, previously generated from donors of both sexes. We showed that APOE3Ch/3Ch astrocytes effectively mitigated tau propagation within iPSC-derived neurons. This study provides important experimental evidence of the characteristic functions exhibited by APOE3Ch/3Ch astrocytes, thereby offering valuable insights for the advancement of novel clinical interventions in AD research.

载脂蛋白 E ( APOE ) 基因的遗传变异影响阿尔茨海默病 (AD) 的发病和进展。 APOE Christchurch ( APOE Ch) 变体已被确定为预防 AD 发病和进展的最重要候选者。在这项研究中，我们从APOE3 / 3健康对照女性 iPSC 中产生了同基因APOE3 Ch/ 3 Ch 人诱导多能干细胞 (iPSC)，并将其诱导为星形胶质细胞。 RNA 表达分析揭示了APOE3 Ch/ 3 Ch 星形胶质细胞诱导炎症细胞因子反应状态的固有弹性。此外，细胞因子治疗改变了APOE3 / 3星形胶质细胞的星形胶质细胞形态，使其更加复杂，但在APOE3 Ch/ 3 Ch 星形胶质细胞中却没有，这表明罕见变体对反应状态的恢复能力。有趣的是，当与 iPSC 衍生的皮质神经元共培养时，我们观察到包含更复杂过程的强烈形态变化，其中APOE3 Ch/ 3 Ch 星形胶质细胞与APOE3 / 3星形胶质细胞相比降低了复杂性。为了评估 tau 传播效应的影响，我们接下来开发了一种复杂而灵敏的检测方法，利用源自人类 iPSC 的皮层神经元，这些神经元之前是从两性供体中产生的。我们发现APOE3 Ch/ 3 Ch 星形胶质细胞有效地减轻了 iPSC 衍生神经元内的 tau 增殖。 这项研究为APOE3Ch/3Ch星形胶质细胞所表现出的特征功能提供了重要的实验证据，从而为 AD 研究中新型临床干预措施的进展提供了宝贵的见解。