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Effect of diets on transgenic and infected mice

The effect of copper diets on transgenic mice was investigated, using TgA20 mice that possess an overexpression of PrPC. For this purpose, we compared the content of copper in different tissues (brain, spleen and thymus) in TgA20 and SV129xC57BL/6. Compared to WT mice, TgA20 mice displayed an increase of copper in the brain and thymus. This increase was not detected in the spleen, although PrPC was expressed and no difference was observed for zinc content in the different tissues. In the course of this experiment, total copper was measured, i.e. intracellular and extracellular copper which can be free or chelated by proteins at the cell surface. Taking into account that the PrPC protein chelates copper and that, in TgA20, PrPC is overexpressed, this suggests that the amount of free copper is decreased, creating a deficit in this cation, which is known to play a crucial role in the regulation of the redox balance.

To test this hypothesis, we increased the pool of free copper by a dietary supplementation with copper (see material and methods). TgA20 mice supplemented in copper displayed a dramatic increase in their thymus size and thymocyte number. Whereas the increase is only 1.7 fold with control mice (189 million cells in treated mice vs 110.4 million), we observed a 9.7 fold increase in TgA20 mice (32.9 million cells vs 3.4 million). To determine whether the observed increase in cell number associated with a resumption of thymocyte maturation, we analyzed by FACS the partition of the DN versus DP compartments of 4-week old control or supplemented TgA20 and WT mice. With copper supplemented TgA20 mice, we systematically observed an increase in the percentage of DP cells and, conversely, a decrease in the number of DN cells compared to control TgA20 mice. The SP subpopulations remained more or less stable. The same experiment was done with WT mice and no significant changes were noted as compared with control mice. Thus, copper supplemented TgA20 mice show a phenotype that comes closer to that of SV129xC57BL/6 mice. It is also noteworthy that the TCR positive cells were also affected by copper supplementation, decreasing from 26.8% to 21.8%. This copper diet investigation on transgenic suggests that the partial blockage observed in TgA20 mice is linked to a deficit in free copper since thymic differentiation restarts after copper addition.

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