Reducing PI4KIIIα Levels or Activity Limits Tau Seed Internalization and Assembly in Human Cortical Neurons

Tau protein aggregation and spreading are central features of neurodegenerative diseases such as Alzheimer's disease and frontotemporal dementia. Here, we investigated the role of phosphatidylinositol 4-kinase type IIIα (PI4KIIIα) in regulating tau propagation. We first used tau biosensor cells to demonstrate that both pharmacological inhibition and genetic reduction in PI4KIIIα effectively reduce the seeding of tau aggregation by extracellular seeds. To extend these findings to a more physiologically relevant system, we generated induced pluripotent stem (iPS) cell-derived cortical neurons carrying pathogenic MAPT mutations. These neurons rapidly acquired tauopathy-associated features, including expression of disease-relevant isoforms such as 4R tau, thereby enabling in vitro modeling of tau pathology. Using this model, we established phenotypic assays to monitor tau propagation and aggregation and applied them to test candidate small molecules. Notably, inhibition of PI4KIIIα consistently reduced seeding of tau assemblies in human neurons, highlighting this kinase as an important player in the seeding of tau pathology. Collectively, our work identifies PI4KIIIα as a regulator of tau pathology and provides new experimental platforms to dissect the molecular mechanisms of tau propagation. These findings open potential avenues for the development of strategies to slow or prevent tau-mediated neurodegeneration in the central nervous system.