Fang Haohui, Liao Xiangyu, Bullen C Korin, Pu Ruoyan, Wang Hu, Condoleo Juliana, Chear Sueanne, Chen Xueyi, Zhang Yanjun, Zhang Sonya, Huo Da, Lissit Kadia, Yang Alina, Jarvis Kateri, Neifert Stewart, Huang Yuejia, Bishai William, Jain Sanjay K, Dawson Ted M, Dawson Valina L, Xu Jin-Chong
Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Present Address: Columbia University, New York, USA.
bioRxiv. 2025 May 9:2025.05.08.652864. doi: 10.1101/2025.05.08.652864.
The APOE gene is a major genetic determinant of neurovascular and immune function, yet the mechanisms by which its isoforms modulate brain vulnerability to pathogenic stress remain incompletely understood. Here, we employ isogenic human iPSC-derived immune-vascularized-Forebrain Organoid-based Multicellular Assembled Cerebral Organoids (FORMA-COs)-to dissect isoform-specific responses to a clinically relevant viral challenge. We find that APOE2/2 and APOE4/4 FORMA-COs exhibit heightened viral RNA burden and distinct neuroinflammatory profiles compared to APOE3/3. Specifically, APOE4/4 promotes IL-1α and VEGFA induction, whereas APOE2/2 leads to elevated TNF-β and VEGFA protein accumulation, indicating divergent pathways of injury. Integrated transcriptomic analyses, combined with known and predicted APOE protein-protein interaction networks, reveal genotype-dependent enrichment of cytokine signaling, angiogenic remodeling, and immune dysregulation. In vivo validation using humanized mouse models corroborates APOE genotype-specific vascular remodeling, microglial activation, and oligodendrocyte perturbation. These findings demonstrate that APOE genotype confers context-specific susceptibility to neuroimmune and vascular injury, providing insight into genetic risk mechanisms underlying infection-related and neurodegenerative brain disorders.
APOE基因是神经血管和免疫功能的主要遗传决定因素，但其异构体调节大脑对致病应激易感性的机制仍未完全清楚。在此，我们采用基于同基因人诱导多能干细胞衍生的免疫血管化前脑类器官的多细胞组装脑类器官（FORMA-COs），来剖析异构体对临床相关病毒攻击的特异性反应。我们发现，与APOE3/3相比，APOE2/2和APOE4/4 FORMA-COs表现出更高的病毒RNA负荷和不同的神经炎症特征。具体而言，APOE4/4促进IL-1α和VEGFA的诱导，而APOE2/2导致TNF-β和VEGFA蛋白积累增加，表明损伤途径不同。综合转录组分析，结合已知和预测的APOE蛋白质-蛋白质相互作用网络，揭示了细胞因子信号传导、血管生成重塑和免疫失调的基因型依赖性富集。使用人源化小鼠模型进行的体内验证证实了APOE基因型特异性血管重塑、小胶质细胞激活和少突胶质细胞扰动。这些发现表明，APOE基因型赋予了对神经免疫和血管损伤的背景特异性易感性，为感染相关和神经退行性脑疾病的遗传风险机制提供了见解。
