迫切需要以患者为基础的、人体细胞模型，该模型集成了仿生BBB、免疫和有髓神经元组分，以便加快对神经系统疾病机制和干预措施的转化相关研究。通过构建仿真脑结构的三维水凝胶，并共培养由患者诱导多能干细胞分化得来的六种主要脑细胞类型，我们已成功制备、表征和应用了一种多细胞一体化的免疫胶质神经-血管模型（miBrain），该模型具有与体内类似的标志特征。作为原理验证，我们利用miBrain模拟了与APOE4基因风险相关的阿尔茨海默病病理过程。APOE4 miBrain表现出不同的淀粉样聚集、tau磷酸化和星形胶质细胞GFAP表达。与器官样体内胶质细胞和神经元的共同命运规格不同，miBrain以模块化系统集成了独立分化的细胞类型，对阐明细胞类型对发病机制的特定贡献具有独特的实用性。我们在此利用这一特性发现，风险因子APOE4在星形胶质细胞中通过与微胶质细胞的相互作用促进了tau致病过程和神经元调控失调。我们开发、表征和利用了一种新的患者特异性脑模型，该模型集成了BBB、神经元、免疫和胶质组分，用于模拟与阿尔茨海默病相关的病理过程和APOE4基因风险。

Patient-specific, human-based cellular models that integrate biomimetic BBB, immune, and myelinated neuron components are critically needed to enable translationally relevant and accelerated discovery of neurological disease mechanisms and interventions. By engineering a brain-mimicking 3D hydrogel and co-culturing all six major brain cell types derived from patient iPSCs, we have constructed, characterized, and utilized a multicellular integrated brain (miBrain) immuno-glial-neurovascular model with in vivo- like hallmarks. As proof of principle, here we utilized the miBrain to model Alzheimer's Disease pathologies associated with APOE4 genetic risk. APOE4 miBrains differentially exhibit amyloid aggregation, tau phosphorylation, and astrocytic GFAP. Unlike the co-emergent fate specification of glia and neurons in organoids, miBrains integrate independently differentiated cell types in a modular system with unique utility for elucidating cell-type specific contributions to pathogenesis. We here harness this feature to identify that risk factor APOE4 in astrocytes promotes tau pathogenesis and neuronal dysregulation through crosstalk with microglia.A novel patient-specific brain model with BBB, neuronal, immune, and glial components was developed, characterized, and harnessed to model Alzheimer's Disease-associated pathologies and APOE4 genetic risk.