The distribution of histopathology in the old NT mouse was extensive, with robust staining being seen in cells in the EC, as well as in the subiculum. Staining was also extensive in the CA1, but to a lesser extent in the DG GC layer. In general, the distribution of silver-staining matched that seen with the MC1 antibody more closely than that seen with the CP27 or AT8 antibodies, suggesting that it is the conformational change in tau recognized by MC1 that is recognized by the silver stain. Interestingly, MC1 immunoreactivity was robust in neurites in the young NT mice but these mice were negative for silver staining. Therefore the silver stain recognizes a more advanced conformational abnormality that lies between pre-tangle MC1 immunoreactivity seen in the young mice, and the overt conformational change recognized by thioS, which in the old mice,Isoastragaloside-II is restricted to cells in the MEC. The reason for this apparent increase is unknown but if it is significant in a larger sample group, it could reflect a feedback mechanism whereby tau transcription is upregulated if tau is losing its ability to perform its’ normal function as it accumulates in the cytosol in the Tau+ DG GCs. The apparent increase in tau levels in old compared to young samples could reflect an age-dependent increase in transcription, or it could simply represent inter-animal variability. Despite the absence of detectable human tau protein immunoreactivity in the tau negative DG GCs from young or old NT mice; human tau mRNA was identified in cells from three separate experiments suggesting that transgene expression was slightly leaky. To further examine whether ectopic expression in the DG GCs could explain the accumulation of protein at old age, we examined mice from two other crosses to the neuropsin tTA activator mouse. The first cross was to a reporter gene expressing LacZ with a nuclear localization signal to restrict the cellular distribution of the reporter to the nucleus of the cell in which it was produced. As shown in Fig. 8E,Astragaloside-II positive staining for LacZ was restricted to very few cells in the DG GC layer. The second cross was to a mutant APP responder line. When crossed to the neuropsin-tTA activator, this mouse expresses APP predominantly in the EC as expected, but due to secretion of Ab, plaques accumulate in regions outside of the EC, including layers of the DG. Of note, the cells of the DG GC layer did not accumulate APP/Ab supporting our observations that ectopic expression of responder genes in this cell layer is negligible. Therefore, despite our findings of some human tau mRNA in DG GCs, ectopic expression in these cells is very limited and unlikely to account for the extensive immunolabeling with human tau specific antibodies seen in the old mice. As we pooled many DG GCs and analysis of mRNA levels by qPCR is extremely sensitive, the actual number of cells contributing the human tau mRNA could be a very low percentage of the total that were human tau protein positive. How human tau protein accumulating in DG GCs that were likely to be human tau mRNA negative was derived is unknown, but it is possible that tau was released from cells originating in the EC, and internalized by DG GCs synapsing on to them. In support of this mechanism, a recent study has shown that tau can be released from cells via exosomes and tau positive exosomes have been identified in human CSF from AD patients. Heart transplantation is a life saving procedure for patients with end-stage heart failure. However, techniques for heart preservation have changed very little over decades. Current hypothermic preservation is still limited to 4–6 hours, not much better than what was obtained five decades ago. To increase myocardial survival times, various additives have been proposed, but the results have not been conclusive.