Analysis of A?-induced neurotoxicity and microglial responses in simple two- and three-dimensional human iPSC-derived cortical culture systems

The extracellular accumulation of amyloid-beta (A beta) in plaques and associated neurodegeneration are the pathological hallmarks of Alzheimer's disease (AD). These plaques are surrounded by microglia-the resident tissue macrophages of the brain parenchyma that originate from primitive macrophages from the embryonic yolk sac. Microglia, including a unique subpopulation called disease-associated microglia (DAM), are strongly implicated in AD pathology; however, their exact function and physiology remain largely unknown. Notably, simple cell and tissue culture systems that adequately recreate the brain microenvironment and can simulate critical aspects of AD pathology could fundamentally contribute to elucidating microglial function in disease development and progression. Thus, we added human-induced pluripotent stem cell (hiPSC)-induced primitive macrophages (hiMacs) to hiPSC-induced cortical neurons (cell model) and cortical organoids (tissue model). The treatment of these culture systems with the O-acyl isopeptide of A beta 1_ 42, which reverts to natural extracellular A beta 1_ 42 at neutral pH and starts self-aggregation, caused the degeneration of hiPSC-induced cortical neurons in 2D culture and within cortical organoid cultures. Notably, the hiMacs phagocytosed extracellular A beta and exhibited a DAM-like phenotype. In both cell and tissue organoid culture systems, neurodegeneration was attenuated by the addition of hiMacs. Moreover, in cortical organoids, A beta plaques formed more circular and fewer hotspot-like morphological structures in the vicinity of hiMacs. These findings demonstrate the utility of simple hiPSC-induced cortical cell and tissue culture systems supplemented with hiMacs for elucidating critical

Automated summary

The extracellular accumulation of amyloid-beta (A beta) in plaques and associated neurodegeneration are the pathological hallmarks of Alzheimer's disease (AD). Microglia, including a unique subpopulation called disease-associated microglia (DAM), are strongly implicated in AD pathology; however, their exact function and physiology remain largely unknown. Researchers demonstrated that hiMacs, a type of induced macrophages derived from hiPSC, can phagocytose extracellular A beta and exhibit a DAM-like phenotype. Adding hiMacs to cell and tissue culture systems attenuated neurodegeneration and altered the morphology of A beta plaques.