Microglial APOE3 Christchurch protects neurons through suppression of ferroptosis in a human iPSC-derived Alzheimer’s disease model

Alzheimer's Disease (AD) is the most prevalent neurodegenerative disorder characterized by extracellular amyloid plaque and neuronal tangle formation. A 2019 study discovered an association between the APOE3 Christchurch (APOE3Ch) variant and delayed AD progression in a PSEN1 mutation carrier. However, whether the APOE3Ch variant is causal to the delayed onset of AD and what is the underlying mechanism remains to be explored. In this study, we established neuron-microglia cocultures and neuroimmune organoids using CRISPR/Cas9-edited isogenic APOE3 and APOE3Ch microglia derived from human induced pluripotent stem cells (hiPSCs) along with PSEN1 mutant neurons or brain organoids. We show that APOE3Ch microglia exhibit enhanced phagocytic capacity and increased Tau clearance in neuron-microglia co-cultures. Moreover, APOE3Ch microglia were able to reduce phosphorylated Tau levels in PSEN1 mutant brain organoids. We also demonstrated that APOE3Ch microglia could preserve neural network activity in co-cultured PSEN1 neurons when challenged with synaptosomes prepared from AD patient brains. RNA-seq analysis identified phagocytosis and ferroptosis among pathways of differentially expressed genes from APOE3 and APOE3Ch microglia. Subsequent validation analyses established a causal link between reduced ferroptosis and enhanced phagocytosis including Tau clearance by APOE3Ch microglia, providing mechanistic insights into the neuroprotective role of APOE3Ch microglia. These findings together demonstrate that the APOE3Ch variant plays a causal role in microglial neuroprotection which can be exploited in therapeutic development for AD.