摘要：SummaryTau pathobiology has emerged as a key component underlying Alzheimer's disease (AD) progression; however, human neuronalin vitromodels have struggled to recapitulate tau phenomena observedin vivo. Here, we aimed to define the minimal requirements to achieve endogenous tau aggregation in functional neurons utilizing human induced pluripotent stem cell (hiPSC) technology. Optimized hiPSC-derived cortical neurons seeded with AD brain-derived competent tau species or recombinant tau fibrils displayed increases in insoluble, endogenous tau aggregates. Importantly,MAPT-wild type andMAPT-mutant hiPSC-neurons exhibited unique propensities for aggregation dependent on the seed strain rather than the repeat domain identity, suggesting that successful templating of the recipient tau may be driven by the unique conformation of the seed. Thein vitromodel presented here represents the first successful demonstration of combining human neurons, endogenous tau expression, and AD brain-derived competent tau species, offering a more physiologically relevant platform to study tau pathobiology.Graphical abstractDisplay OmittedHighlights•Seeded tau aggregation in hiPSC-neurons does not require tau overexpression•Tau aggregation is concentration, time, and maturation dependent•Successful templating requires compatibility between neuronal tau and added seeds•Endogenous tau aggregates exhibit properties consistent with pathological tauMolecular neuroscience; Cellular neuroscience; Stem cells research
