Microglia-astrocyte interplay mitigates Aβ toxicity in a novel human 3D neurosphere model of Alzheimer's Disease
Microgliosis and astrogliosis characteristically occur at A{beta} 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 A{beta}-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 A{beta} 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 A{beta} and facilitate neuroprotection. Our findings further support a pivotal role for microglia in modulating astrocyte A{beta} responses by inducing AD-associated gene expression in astrocytes, including the upregulation of APOE, crucial for A{beta} clearance. This model, highlighting the neuroprotective potential of microglia-astrocyte interactions, offers a novel platform for exploring AD mechanisms and novel therapeutic strategies.