02009nas a2200265   4500000000100000008004100001260001500042100001700057700001300074700002000087700001600107700001300123700001600136700001900152700001500171700001600186700001500202700002200217700001300239245013400252856005500386300001300441490000700454520128200461       2025                            d  c2025-08-221 aChunhui Tian1 aZheng Ao1 aJonas Cerneckis1 aHongwei Cai1 aLei Chen1 aHengyao Niu1 aKazuo Takayama1 aJungsu Kim1 aYanhong Shi1 aMingxia Gu1 aTakahisa Kanekiyo1 aFeng Guo00aUnderstanding monocyte-driven neuroinflammation in Alzheimer’s disease using human cortical organoid microphysiological systems  uhttps://www.science.org/doi/10.1126/sciadv.adu2708  aeadu27080 v113 aIncreasing 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 IL1B and CCL3 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.