Low, but detectable levels of immunoreactivity were seen in the outer third of the molecular layer which represents terminals from neurons originating in the LEC. Some human tau was seen in cells in the hilus, most likely in mossy cells. Notably, human tau did not accumulate in DG GCs in young NT mice. Old NT mice however showed a very different distribution of human tau. Robust accumulation of human tau was now seen in DG GCs and increased accumulation of human tau was seen in layers 1, 2 and 4. The appearance of tau in DGGCs strongly supports the idea that tauopathy initiated in the EC can spread between cells that are connected, but physically separated by a synapse. Interestingly, the perforant pathway endzone in layer 3 was significantly depleted of tau which coincided with accumulation in originating cell bodies in the MEC. This apparent relocalization of tau from axons to somatodendritic compartments is one of the earliest events in the pathological cascade of early Alzheimer’s disease. Tauopathy in AD is usually staged using the antibody AT8. This antibody recognizes phosphorylated epitopes S202/205 that are abundant in tau from AD brain, but not normal brain. In young NT mice,Astragaloside-I AT8 immunoreactive tau was mainly concentrated in the EC with no staining visible in the hippocampal subfields. Cell body staining was predominant with relatively less staining seen in neurites. In old NT mice, there was considerably more neurite staining throughout the EC, and in all fields of the hippocampus, with cell body immunoreactivity being seen in scattered neurons that were most prominent in pyramidal cells in the CA1 and in DG GCs. As for MC1, in the old mice, additional cell body staining was apparent in the deeper layers of the EC, and in cells in the perirhinal and parietal cortices. The control mouse was essentially negative for this antibody. Overall, the pattern of staining, including extensive staining of cell bodies and neurites throughout the EC and hippocampus was reminiscent of that described for early Braak stages of AD. Although the exact type of tau associated with functional impairment and degeneration is not known, the accumulation of insoluble,Astragaloside conformationally abnormal, hyperphosphorylated tau into mature neurofibrillary tangles in the somatodendritic cell compartment is generally associated with more severe pathology, degeneration and cell death. To test whether mature tangles had formed in the NT mice, we examined tissue sections stained with thioflavin S, a dye that binds to proteins in a b- sheet conformation, indicative of tau in mature tangles. Special care was taken to mask lipofuscin fluorescence which is significant in old mice. A small number of neurons restricted to the MEC were positive for thioS in old NT mice. Young NT and old control mice were essentially negative. Not all of the tau immunoreactive neurons in the MEC of old NT mice were thioS positive, and cells in the LEC, CA1 and DG GC layer were thioS negative, as were neurites and axonal terminals in the perforant pathway. As cells with the highest level of human tau occur in the MEC, the lack of staining in other areas is most likely explained by the lower tau levels rather than by regional sensitivity to tangle formation, but the latter interpretation cannot be ruled out in these studies. Altered conformation of proteins can also be visualized by silver staining using one of several methods. Argyophilic plaques, tangles and neurites are abundant in the human AD brain. Abundant, argyrophilic cell body and neurite staining was also seen in the old, but not the young NT mice, and it was related to tauopathy development rather than aging as parallel-processed, old littermate control mice were negative.