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bioRxiv · 10.1101/2025.10.17.683162

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

Sherman, E.·Qiu, K.·Roberts, R.·Shichman, L.·Li, S.·Sun, H.·Ide, L.·Tucker, A.·lee, s.·Gniadzik, W.·Shin, J.-B.·Sol-Church, K.·Kapur, J.·Zhang, A.·Erisir, A.·Jiang, L.·Alzheimer's Disease Neuroimaging Initiative,
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Abstract

Alzheimers 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-{beta} oligomer exposure. After four weeks, AD-Masteroids exhibited hallmark pathologies, including extracellular amyloid-{beta} 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-{beta} 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. HighlightsO_LIThe 3D human neuron-glia assembloid ("Masteroid"), composed of neurons, astrocytes, microglia, and oligodendrocytes, faithfully recapitulates human brain ultrastructure and intercellular interactions. C_LIO_LIExposure to oligomeric tau and A{beta} induced hallmark Alzheimers pathologies, including amyloid deposition, tau aggregation, neurodegeneration, and gliosis. C_LIO_LIThe APOE4 genotype exacerbated all pathological features, highlighting its role in driving multicellular interactions that accelerate disease progression. C_LIO_LIThe IGF signaling axis was identified as a key mediator of A{beta}- and tau-induced pathology and a potential therapeutic target. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=183 SRC="FIGDIR/small/683162v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@f91740org.highwire.dtl.DTLVardef@165726eorg.highwire.dtl.DTLVardef@13b957forg.highwire.dtl.DTLVardef@d40307_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Sherman, E., Qiu, K., Roberts, R., Shichman, L., Li, S., Sun, H., Ide, L., Tucker, A., lee, s., Gniadzik, W., Shin, J.-B., Sol-Church, K., Kapur, J., Zhang, A., Erisir, A., Jiang, L., Alzheimer's Disease Neuroimaging Initiative,. 2025-10-19. Modeling Alzheimer's Disease with APOE4 Neuron-Glial Brain Assembloids Reveals IGFBPs as Therapeutic Targets. https://doi.org/10.1101/2025.10.17.683162

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