Modeling Alzheimer's Disease with APOE4 Neuron-Glial Brain Assembloids Reveals IGFBPs as Therapeutic Targets.

UNLABELLED: Alzheimer's disease (AD) research has been hindered by the lack of models that faithfully recapitulate the full profile of disease progression in a human genetic background. We developed a 3D assembloid model ("Masteroid") using iPSC-derived neurons, astrocytes, and microglia from APOE4/4 and isogenic control lines. Neurons were seeded with tau oligomers, then combined with astrocytes and microglia to form mature 3D Masteroids, followed by amyloid-β oligomer exposure. After four weeks, AD-Masteroids exhibited hallmark pathologies, including extracellular amyloid-β deposits, intracellular tau aggregation, neurodegeneration, astrogliosis, and microglial activation, with APOE4 exacerbating all phenotypes. Single-cell RNA sequencing further identified novel roles of IGFBP pathways in amyloid-β and tau-mediated pathology. This innovative platform provides a robust system to dissect cellular and molecular mechanisms of AD progression and offers a powerful tool for therapeutic discovery.

HIGHLIGHTS: The 3D human neuron-glia assembloid ("Masteroid"), composed of neurons, astrocytes, microglia, and oligodendrocytes, faithfully recapitulates human brain ultrastructure and intercellular interactions.Exposure to oligomeric tau and Aβ induced hallmark Alzheimer's pathologies, including amyloid deposition, tau aggregation, neurodegeneration, and gliosis.The APOE4 genotype exacerbated all pathological features, highlighting its role in driving multicellular interactions that accelerate disease progression.The IGF signaling axis was identified as a key mediator of Aβ- and tau-induced pathology and a potential therapeutic target.