Human Induced Pluripotent Stem Cell-Derived Neural Cells from Alzheimer's Disease Patients Exhibited Different Susceptibility to Oxidative Stress

The cell-type-specific response of neural cells to oxidative stress, a crucial mechanism for accelerating aging and cognitive dysfunction in Alzheimer's disease (AD), is still far from understood. Here, we employed human-induced pluripotent stem cells (hiPSCs)-derived neural stem cells (hiPSC-NSCs), neurons (hiPSC-Neurons), and microglia-like cells (hiPSC-MGLs) from sporadic AD (sAD) patients, age-matched cognitive normal controls (CNCs), and young subjects to observe human neural cell-type response to H 2 O 2 stimulation. Without H 2 O 2 exposure, reactive oxygen species (ROS) cannot be detected in hiPSC-NSCs from all three groups, but the viability of hiPSC-NSCs from AD patients was significantly lower than those of CNCs and young subjects. There were no significant differences in ROS, viabilities, neurite length, and neurite branch points in hiPSC-Neurons among three groups. No significant differences in viabilities, phagocytosis, and secretion of cytokines were observed in hiPSC-MGLs among three groups, but higher ROS levels in sAD hiPSC-MGLs. Under H 2 O 2 exposure, the viability, neurite length, and neurite branch points of hiPSC-Neurons from AD patients reduced more significantly accompanied by more ROS release. H 2 O 2 exposure caused hiPSC-MGLs from AD patients to release more ROS, cytokines, and stronger phagocytosis. Nevertheless, H 2 O 2 exposure had no effect on viability of hiPSC-NSCs. Our results showed hiPSC-Neurons and hiPSC-MGLs were more sensitive to H 2 O 2 than hiPSC-NSCs, which indicated the different response styles of hiPSC-NSCs, hiPSC-Neurons, and hiPSC-MGLs to oxidative stress. HiPSC-derived neural cells from AD patients suffered more severe injury from H 2 O 2 than those of CNCs and young subjects, indicating that the vulnerability to oxidative stress of AD patients can be recapitulated in hiPSCs.