Microglia-astrocyte interplay mitigates Aß toxicity in a novel human 3D neurosphere model of Alzheimer's Disease

Microgliosis and astrogliosis characteristically occur at Aß plaques in the brains of Alzheimer's disease (AD) patients although the impact of gliosis in AD is poorly understood. We studied the impact of Aß-induced gliosis using human induced pluripotent stem cell (hiPSC)-derived 3D neurospheres (hiNS), containing only astrocytes and neurons versus hiNS with the addition of iPSC-derived microglia (hiMG). Applying Aß to hiNS containing only astrocytes and neurons triggered pathological features of AD including plaque-like aggregates, reactive astrocytes, oxidative stress, neuronal dysfunction and cell death. In contrast, when hiMG were combined with hiNS, infiltrating hiMG effectively phagocytose Aß and facilitate neuroprotection. Our findings further support a pivotal role for microglia in modulating astrocyte Aß responses by inducing AD-associated gene expression in astrocytes, including the upregulation of APOE, crucial for Aß clearance. This model, highlighting the neuroprotective potential of microglia-astrocyte interactions, offers a novel platform for exploring AD mechanisms and novel therapeutic strategies. Overall design: High-throughput single nuclei transcriptomic profiles of human induced pluripotent stem cell (hiPSC)-derived 3D neurospheres (hiNS), generated by single nuclei RNA sequencing using the 10X Genomics platform.