Brain function in health and disease depends on the interactions between neurons and glial cells. To dissect the underlying molecular mechanisms in a reductionist system, a project led by Kampmann lab graduate student Emmy Li established a 3D co-culture system integrating human iPSC-derived neurons, astrocytes and microglia, and combined it with CRISPR-based genetic screens in specific cell types. A first application uncovered the kinase GSK3beta as a regulator of a response neurons mount to protect against reactive oxygen species generated by high levels of neuronal activity. Glial cells are also protective in this context, but astrocytes with the APOE4 isoform (linked to Alzheimer's disease risk) are less protective than astrocytes with the APOE3 isoform (neutral with respect to Alzheimer's disease risk), highlighting a new mechanism by which APOE4 may contribute to Alzheimer's disease.
The findings were published in Neuron, with an iAssembloid image featured on the cover.
Li E, Benitez C, Boggess SC, Koontz M, Rose IVL, Martinez D, Dräger N, Teter OM, Samelson AJ, Pierce N, Ullian EM, Kampmann M. CRISPRi-based screens in iAssembloids to elucidate neuron-glia interactions. Neuron 113(5):701-718. PMID 39814010.
The work was also featured in an article by Alzforum.