Abstract Aggregation of the microtubule-associated protein tau is a defining feature of Alzheimer’s disease and other tauopathies. Tau pathology is believed to be driven by both free tau aggregates and tau carried within exosomes, which propagate trans-synaptically and induce tau pathology in recipient neurons by a corrupting process of seeding. Here, we performed a genome-wide CRISPRi screen in tau biosensor cells and identified cellular regulators shared by both mechanisms of tau seeding. The top validated regulators are ANKLE2, BANF1, NUSAP1, EIF1AD, and VPS18, which work as factors that restrict tau aggregation initiated by both exosomal and vesicle-free tau seeds. Interestingly, ANKLE2 and BANF1 more robustly affected exosomal tau seeding than free aggregates. Lastly, validation studies revealed that several of the identified protein hits are downregulated in the brains of Alzheimer’s patients, suggesting that their decreased activity may be required for the emergence or progression of tau pathology in the human brain.

Genome-wide CRISPRi screening reveals regulators of Alzheimer’s tau pathology shared between exosomal and vesicle-free tau seeds