Patient-derived tau-seeded human neuronal chimeras recapitulate mature Alzheimer's tau pathology and uncover human-specific neuronal vulnerability

Tau pathology is a central hallmark of Alzheimers disease (AD) and strongly correlates with cognitive decline, yet the development of tau-targeted therapies has been hindered by the inability of existing models to capture human-specific disease features, particularly the mature forms of AD tau pathology. Moreover, species-specific mechanisms underlying tau pathology remain poorly understood. Here, we establish a patient-derived tau-seeded human neuronal chimera model by transplanting human pluripotent stem cell (hPSC)-derived neural progenitor cells into neonatal mouse brains, followed by intracerebral injection of pathological tau seeds from postmortem AD brains. Human neurons matured in vivo and recapitulated adult human tau features, including all six isoforms with an approximately 1:1 3R:4R ratio. Upon seeding, aged human neurons without FTD mutations faithfully developed robust, mature AD tau pathology, including neurofibrillary tangles (NFTs) and neuropil threads composed of paired helical filaments (PHFs) and straight filaments (SFs) containing 3R and 4R tau, closely mirroring advanced-stage AD. This pathology accumulated and spread across anatomically connected regions, accompanied by neurodegeneration, elevated plasma pTau-217, and memory deficits. Strikingly, tau pathology was largely restricted to human neurons, revealing a pronounced human-specific vulnerability. Mechanistically, snRNA-seq showed that human neurons exhibited higher basal expression of tau-uptake genes and widespread synaptic suppression following tau exposure, whereas mouse neurons remained transcriptomically resilient. Finally, the familial AD mutation PSEN2 N141I exacerbated tau pathology and synaptic loss in human neurons. Together, this model recapitulates the molecular, structural, and functional hallmarks of mature AD tau pathology in human neurons in vivo and reveals intrinsic, species-specific vulnerability, providing a human-relevant in vivo platform for mechanistic studies and therapeutic development.