Tian Chunhui, Ao Zheng, Cerneckis Jonas, Cai Hongwei, Chen Lei, Niu Hengyao, Takayama Kazuo, Kim Jungsu, Shi Yanhong, Gu Mingxia, Kanekiyo Takahisa, Guo Feng
Department of Intelligent Systems Engineering, Indiana University Bloomington, IN 47405, USA.
Department of Neurodegenerative Diseases, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
Sci Adv. 2025 Aug 22;11(34):eadu2708. doi: 10.1126/sciadv.adu2708.
Increasing evidence strongly links neuroinflammation to Alzheimer's disease (AD) pathogenesis. Peripheral monocytes are crucial components of the human immune system, but their contribution to AD pathogenesis is still largely understudied partially due to limited human models. Here, we introduce human cortical organoid microphysiological systems (hCO-MPSs) to study AD monocyte-mediated neuroinflammation. By culturing doughnut-shape organoids on 3D-printed devices within standard 96-well plates, we generate hCO-MPSs with reduced necrosis, minimized hypoxia, and improved viability. Using these models, we found that monocytes from AD patients exhibit increased infiltration ability, decreased amyloid-β clearance capacity, and stronger inflammatory response than monocytes from age-matched control donors. Moreover, we observed that AD monocytes induce pro-inflammatory effects such as elevated astrocyte activation and neuronal apoptosis. Furthermore, the marked increase in and expression underscores their pivotal role in AD monocyte-mediated neuroinflammation. Our findings provide insight into understanding monocytes' role in AD pathogenesis, and our lab-compatible MPS models may offer a promising way for studying various neuroinflammatory diseases.
越来越多的证据有力地将神经炎症与阿尔茨海默病（AD）的发病机制联系起来。外周单核细胞是人类免疫系统的关键组成部分，但由于人类模型有限，它们对AD发病机制的贡献在很大程度上仍未得到充分研究。在这里，我们引入人类皮质类器官微生理系统（hCO-MPSs）来研究AD单核细胞介导的神经炎症。通过在标准96孔板内的3D打印装置上培养甜甜圈形状的类器官，我们生成了坏死减少、缺氧最小化且活力提高的hCO-MPSs。使用这些模型，我们发现与年龄匹配的对照供体的单核细胞相比，AD患者的单核细胞表现出更强的浸润能力、降低的淀粉样β清除能力和更强的炎症反应。此外，我们观察到AD单核细胞会诱导促炎作用，如星形胶质细胞活化增强和神经元凋亡。此外，[此处原文缺失具体指标]表达的显著增加突出了它们在AD单核细胞介导的神经炎症中的关键作用。我们的研究结果为理解单核细胞在AD发病机制中的作用提供了见解，并且我们实验室兼容的MPS模型可能为研究各种神经炎症性疾病提供一种有前景的方法。
