The ε4 allele of APOE-encoding apolipoprotein (ApoE) is one of the strongest genetic risk factors for Alzheimer’s disease (AD). One of the overarching questions is whether and how this astrocyte-enriched risk factor initiates AD-associated pathology in neurons such as amyloid-β (Aβ) accumulation. Here, we generate neurons and astrocytes from isogenic human induced pluripotent stem cells (hiPSCs) carrying either APOE ε3 or APOE ε4 allele and investigate the effect of astrocytic ApoE4 on neuronal Aβ production. Secretory factors in conditioned media from ApoE4 astrocytes significantly increased amyloid precursor protein (APP) levels and Aβ secretion in neurons. We further found that increased cholesterol secretion from ApoE4 astrocytes was necessary and sufficient to induce the formation of lipid rafts that potentially provide a physical platform for APP localization and facilitate its processing. Our study reveals the contribution of ApoE4 astrocytes to amyloidosis in neurons by expanding lipid rafts and facilitating Aβ production through an oversupply of cholesterol.

APOE编码载脂蛋白 (ApoE) 的 ε4 等位基因是阿尔茨海默病 (AD) 最强的遗传风险因素之一。最重要的问题之一是，这种富含星形胶质细胞的危险因素是否以及如何引发神经元中与 AD 相关的病理，例如淀粉样蛋白-β (Aβ) 的积累。在这里，我们从携带APOE ε3 或APOE ε4 等位基因的同基因人类诱导多能干细胞 (hiPSC) 中产生神经元和星形胶质细胞，并研究星形胶质细胞 ApoE4 对神经元 Aβ 产生的影响。 ApoE4 星形胶质细胞条件培养基中的分泌因子显着增加了神经元中淀粉样前体蛋白 (APP) 的水平和 Aβ 分泌。我们进一步发现，ApoE4 星形胶质细胞胆固醇分泌的增加对于诱导脂筏的形成是必要且充分的，脂筏可能为 APP 定位提供物理平台并促进其加工。我们的研究揭示了 ApoE4 星形胶质细胞通过扩张脂筏并通过过量供应胆固醇促进 Aβ 产生而对神经元淀粉样变性做出贡献。