Alzheimer's disease (AD) induces amyloid-β (Aβ) accumulation and neurodegeneration in the brain. Microglia are immune cells in the brain, and their origin is macrophages in the foetal yolk sac. Aβ plaques are surrounded by microglia and a unique microglial subpopulation, disease-associated microglia (DAM), appears in the AD brain. Simple and accurate cell culture systems that can reproduce the pathological microenvironment of the AD brain are needed to elucidate the pathophysiological role of microglia, including DAMs. In this study, we established a co-culture system of human induced pluripotent stem (hiPS) cells derived cortical neurons or organoids with microglial progenitor cells (hiMacs). O-acyl isopeptide Aβ_1-42 stably forms highly toxic oligomers and were used to analyse Aβ stress. Although Aβ induced marked neurodegeneration in cortical neurons and organoids, adding hiMacs suppressed it. hiMacs phagocytosed Aβ and showed DAM-like transitions. Furthermore, jagged Aβ plaques were formed with hot spot-like structures in cortical organoids, but were smoother surfaces near hiMacs. hiMacs showed neuroprotective effects might be phagocytosis of Aβ and morphological modification of Aβ plaques. The co-culture model of cortical neurons and organoids with hiMacs is helpful for elucidating microglial function in AD pathology.