As shown in Fig. 1, the EC is monosynaptically connected to other hippocampal subregions and it is trans-synaptically connected with affected regions in the temporal and parietal lobes. One of the most intriguing and poorly explored questions in the field is whether pathology, and/or dysfunction of the EC initiates anatomical progression of the disease, or whether pathology and/or dysfunction in extrahippocampal areas develops independently, and is unrelated to events occurring in the EC. There are a number of interesting, albeit circumstantial observations that support the trans-synaptic spread hypothesis for AD both intermsof pathology development and functional outcome. First, by simply charting the anatomical distribution of the pathology in human post-mortem tissue, the affected areas appear to be transsynaptically linked. Second, functional imaging studies in non-human primates have shown that lesioning the rhinal cortex causes secondary dysfunction in the temporal and parietal lobes. Currently available AD transgenic mouse models do not allow for studies of disease circuitry and progression as they generally overexpress APP Bullatine-B in inappropriate areas, or at high levels throughout the brain making it hard to identify temporal and spatial progression between vulnerable areas. To address this shortcoming, we have generated a transgenic mouse model with restricted expression of pathological human tau that predominates in the entorhinal cortex. Wehaveperformed a detailed histopathological analysis of the mice to map the change in distribution of tauopathy as the mice age. Our data support a temporal and spatially defined mechanism of trans-synaptic spread along anatomically connected networks, between connected and vulnerable neurons that replicates the early stages of AD. In the CA1 and subiculum, the outer molecular layer was labeled extensively, indicating tau in perforant path terminals from layer III cells in both LEC and MEC. Mice expressing only the uninduced tau transgene showed negligible, or very limited immunoreactivity with the antibodies used, and it was usually restricted to the mossy fibers. Some nonspecific staining in the fornix was seen in all mice, with all antibodies. By 22 months of age, the distribution of human tau in old NT mice had changed dramatically to resemble that seen in more affected AD brain tissue. Intense MC1 immunoreactivity was readily detected not only in neurons in the superficial layers of the EC and throughout the subiculum, but in pyramidal neurons in the hippocampus, especially in CA1,Delsoline and also in dentate gyrus granule cells. Somatodendritic staining with MC1 was intense for cells in the MEC. Scattered MC1 positive neuronal cell bodies could also be seen in the perirhinal and the parietal cortices, and more extensively in the deeper layers of the EC. The pattern of staining was reproduced in young and old NT mice using a human specific tau antibody that recognizes all human tau, regardless of phosphorylation or conformation status. Subtle differences in the relative intensity of staining in different areas were observed for different antibodies, especially in the DG GC layer where CP27 staining was more intense and extensive than MC1. This could either indicate differential sensitivity of the antibodies, differential synthesis or clearance of tau forms recognized by the two antibodies, or retarded development of the conformational change in tau recognized by MC1. To assess whether tauopathy could spread across a synapse, we examined cells in the DG that are monosynaptically connected with cells in the EC. Young NT mice showed robust accumulation of CP27 immunoreactive human tau in the endzones of the perforant pathway that originate from neurons in the MEC and terminate in the middle third of the molecular layer of the DG.