This study investigates the trans-synaptic spread of tau pathology in the brain of Alzheimer's disease (AD) patients, focusing on the entorhinal cortex (EC). The researchers generated a transgenic mouse model that expresses pathological human tau specifically in the EC and examined the distribution of tau pathology at different time points. In young mice (10-11 months old), human tau was primarily observed in axons within the superficial layers of the EC and at the terminal zones of the perforant pathway. In older mice (≥22 months old), intense human tau immunoreactivity was detected in neurons in the EC, subiculum, hippocampal pyramidal neurons, and dentate gyrus granule cells. The conformation-specific tau antibody MC1 correlated with the accumulation of argyrophilic material seen in old mice but not in young mice. Axonal human tau immunoreactivity was reduced in old mice, while somatodendritic tau immunoreactivity increased, indicating a relocalization of tau from axons to somatodendritic compartments. This relocalization correlated with the formation of mature tangles in neurons in the EC. The study supports a trans-synaptic mechanism of tau pathology spread along anatomically connected networks, providing a model for testing mechanisms and functional outcomes associated with disease progression.This study investigates the trans-synaptic spread of tau pathology in the brain of Alzheimer's disease (AD) patients, focusing on the entorhinal cortex (EC). The researchers generated a transgenic mouse model that expresses pathological human tau specifically in the EC and examined the distribution of tau pathology at different time points. In young mice (10-11 months old), human tau was primarily observed in axons within the superficial layers of the EC and at the terminal zones of the perforant pathway. In older mice (≥22 months old), intense human tau immunoreactivity was detected in neurons in the EC, subiculum, hippocampal pyramidal neurons, and dentate gyrus granule cells. The conformation-specific tau antibody MC1 correlated with the accumulation of argyrophilic material seen in old mice but not in young mice. Axonal human tau immunoreactivity was reduced in old mice, while somatodendritic tau immunoreactivity increased, indicating a relocalization of tau from axons to somatodendritic compartments. This relocalization correlated with the formation of mature tangles in neurons in the EC. The study supports a trans-synaptic mechanism of tau pathology spread along anatomically connected networks, providing a model for testing mechanisms and functional outcomes associated with disease progression.