This study investigates the trans-synaptic spread of tau pathology in vivo using a transgenic mouse model. The model expresses pathological human tau specifically in the entorhinal cortex (EC), and the distribution of tau pathology is examined at different ages. In young mice (10–11 months), human tau is mainly found in axons within the superficial layers of the EC and at the terminal zones of the perforant pathway. In older mice (>22 months), tau pathology is more widespread, including neurons in the EC, subiculum, hippocampus, and dentate gyrus. The conformation-specific antibody MC1 correlates with the accumulation of argyrophilic material in old mice, while axonal tau immunoreactivity is reduced. Relocalization of tau from axons to somatodendritic compartments and propagation of tauopathy to regions outside the EC are associated with mature tangle formation in EC neurons. These findings support a trans-synaptic mechanism of tau pathology spread along anatomically connected networks between connected and vulnerable neurons. The mouse model recapitulates the early stages of Alzheimer's disease and provides a model for studying disease progression mechanisms and functional outcomes. The study also shows that tauopathy can spread to cells outside the EC, and that human tau mRNA is present in DG granule cells, suggesting that transgene expression may be slightly leaky. However, ectopic expression in these cells is limited and unlikely to account for the extensive immunolabeling seen in old mice. The study concludes that the NT mouse model replicates the spatial and temporal aspects of the earliest stages of Braak staging of tauopathy in Alzheimer's disease, and supports the idea that AD progresses via an anatomical cascade rather than individual events in differentially vulnerable regions. The study also suggests that tau can be released from cells via exosomes, which may contribute to the spread of tau pathology. The findings provide a model for testing mechanisms and functional outcomes associated with disease progression in Alzheimer's disease.This study investigates the trans-synaptic spread of tau pathology in vivo using a transgenic mouse model. The model expresses pathological human tau specifically in the entorhinal cortex (EC), and the distribution of tau pathology is examined at different ages. In young mice (10–11 months), human tau is mainly found in axons within the superficial layers of the EC and at the terminal zones of the perforant pathway. In older mice (>22 months), tau pathology is more widespread, including neurons in the EC, subiculum, hippocampus, and dentate gyrus. The conformation-specific antibody MC1 correlates with the accumulation of argyrophilic material in old mice, while axonal tau immunoreactivity is reduced. Relocalization of tau from axons to somatodendritic compartments and propagation of tauopathy to regions outside the EC are associated with mature tangle formation in EC neurons. These findings support a trans-synaptic mechanism of tau pathology spread along anatomically connected networks between connected and vulnerable neurons. The mouse model recapitulates the early stages of Alzheimer's disease and provides a model for studying disease progression mechanisms and functional outcomes. The study also shows that tauopathy can spread to cells outside the EC, and that human tau mRNA is present in DG granule cells, suggesting that transgene expression may be slightly leaky. However, ectopic expression in these cells is limited and unlikely to account for the extensive immunolabeling seen in old mice. The study concludes that the NT mouse model replicates the spatial and temporal aspects of the earliest stages of Braak staging of tauopathy in Alzheimer's disease, and supports the idea that AD progresses via an anatomical cascade rather than individual events in differentially vulnerable regions. The study also suggests that tau can be released from cells via exosomes, which may contribute to the spread of tau pathology. The findings provide a model for testing mechanisms and functional outcomes associated with disease progression in Alzheimer's disease.