Gu Longjun, Mao Xiangdi, Tian Chunhui, Yang Yang, Yang Kaiyuan, Canfield Scott G, Zhu Donghui, Gu Mingxia, Guo Feng
Department of Intelligent Systems Engineering, Indiana University, Bloomington, IN 47405, USA.
Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
Biomater Sci. 2025 Jun 25;13(13):3650-3661. doi: 10.1039/d5bm00204d.
Alzheimer's disease (AD) is a progressive and neurodegenerative disease, predominantly causing dementia. Despite increasing clinical evidence suggesting the involvement of peripheral immune cells such as monocytes in AD pathology, the dynamic penetration and infiltration of monocytes crossing blood-brain barrier (BBB) and inducing neuroinflammation is largely understudied in an AD brain. Herein, we engineer BBB-like microphysiological system (BBB-MPS) models for recapitulating the dynamic penetration and infiltration of monocytes in an AD patient's brain. Each BBB-MPS model can be engineered by integrating a functional BBB-like structure on a human cortical organoid using a 3D-printed device within a well of a plate. By coculturing these BBB-MPS models with monocytes from AD patients and age-matched healthy donors, we found that AD monocytes exhibit significantly greater BBB penetration and brain infiltration compared to age-matched control monocytes. Moreover, we also tested the interventions including Minocycline and Bindarit, and found they can effectively inhibit AD monocyte infiltration, subsequently reducing neuroinflammation and neuronal apoptosis. We believe these scalable and user-friendly BBB-MPS models may hold promising potential in modeling and advancing therapeutics for neurodegenerative and neuroinflammatory diseases.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，主要导致痴呆。尽管越来越多的临床证据表明外周免疫细胞如单核细胞参与了AD病理过程，但单核细胞穿越血脑屏障（BBB）并引发神经炎症的动态穿透和浸润在AD脑内的研究仍很不足。在此，我们构建了类似血脑屏障的微生理系统（BBB-MPS）模型，以重现AD患者脑内单核细胞的动态穿透和浸润。每个BBB-MPS模型可通过在培养板孔内使用3D打印设备将功能性类似血脑屏障的结构整合到人类皮质类器官上来构建。通过将这些BBB-MPS模型与AD患者和年龄匹配的健康供体的单核细胞共培养，我们发现与年龄匹配的对照单核细胞相比，AD单核细胞表现出显著更强的血脑屏障穿透和脑浸润能力。此外，我们还测试了包括米诺环素和宾达利在内的干预措施，发现它们可以有效抑制AD单核细胞浸润，进而减少神经炎症和神经元凋亡。我们相信这些可扩展且用户友好的BBB-MPS模型在神经退行性和神经炎症性疾病的建模及推进治疗方面可能具有广阔的潜力。
